17-31327718-C-T

Position:

chr17-31327718-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The ENST00000358273.9(NF1):c.5488C>T(p.Arg1830Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1830H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NF1
ENST00000358273.9 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:27O:1

Conservation

PhyloP100: 3.80

Variant links:

Genes affected

NF1 (HGNC:7765): (neurofibromin 1) This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]

NF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in ENST00000358273.9

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-31327718-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NF1. . Gene score misZ 6.5427 (greater than the threshold 3.09). Trascript score misZ 8.4054 (greater than threshold 3.09). GenCC has associacion of gene with neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 17-31327718-C-T is Pathogenic according to our data. Variant chr17-31327718-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 208853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31327718-C-T is described in Lovd as [Pathogenic]. Variant chr17-31327718-C-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3 linkuse as main transcript	c.5488C>T	p.Arg1830Cys	missense_variant	38/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3 linkuse as main transcript	c.5425C>T	p.Arg1809Cys	missense_variant	37/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 linkuse as main transcript	c.5488C>T	p.Arg1830Cys	missense_variant	38/58	1	NM_001042492.3	ENSP00000351015	P1	P21359-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Pathogenic:9Other:1

Pathogenic, no assertion criteria provided	clinical testing	UAB Medical Genomics Laboratory, UAB Medicine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 31, 2019	Variant summary: NF1 c.5425C>T (p.Arg1809Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251906 control chromosomes (gnomAD and publication). c.5425C>T has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 1 (NF1) (Syrbe_2007, Ekvall_2013, Pinna_2015) and Neurofibromatosis-Noonan Syndrome (NFNS) (Ekvall_2013). Authors indicate the variant to cause a mild form presenting with cafe au lait spots with or without freckling or Lisch nodules and no neurofibromas. In addition, one family showed lack of segregation with disease (Nystrom_2008). These data indicate that the variant is very likely to be associated with disease. A functional study, Wallis_2018, found the variant to lower GTP-RAS levels similar to the wild-type protein, but was unable to repress p-ERK/ERK and ELK1 transcriptional activity. Four ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 26, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1809 of the NF1 protein (p.Arg1809Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with neurofibromatosis, neurofibromatosis-Noonan syndrome, and/or Noonan syndrome (PMID: 12807981, 19120036, 24357598, 24789688, 26178382). It has also been observed to segregate with disease in related individuals. This missense change has been observed in at least one individual who was not affected with NF1-related conditions (PMID: 12807981, 19120036). ClinVar contains an entry for this variant (Variation ID: 208853). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NF1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	NHS Central & South Genomic Laboratory Hub	Nov 11, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 24, 2017	The p.Arg1830Cys (also referred to as p.Arg1809Cys on NM_000267.3) variant in NF1 has been reported in >80 probands with clinical features of neurofibromatosis type 1 (NF1) or Noonan syndrome-NF1 syndrome and segregated with disease in >40 relatives (Ars 2003, Nystrom 2008, Ekvall 2014, Rojnueangnit 2015, Pinna 2015, Santoro 2015). Most patients with this variant have a milder form of NF1, with skin abnormalities but no neurofibromas or tumors aside from lipomas in some individuals. In some families, however, cafe au lait spots were present in relatives who did not have the variant (Nystrom 2008, Rojnueangnit 2015). This variant has also been reported in ClinVar (Variation ID# 208853). Computational prediction tools and conservation analysis suggest that the p.Arg1830Cys variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for NF1 in an autosomal dominant manner but is expected to result in a milder phenotype. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 02, 2024	- -

not provided

Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 20, 2022	PP1_strong, PP2, PP3, PP4, PP5, PM2, PM6_very_strong, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	NF1: PM2, PM5, PM6, PS4:Moderate, PP2, PP3 -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 02, 2020	p.Arg1809 missense variants account for approximately 1% of individuals with neurofibromatosis type 1 (Rojnueangnit et al., 2015); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27322474, 12807981, 26457592, 25533962, 27171602, 28135719, 19120036, 24789688, 28191890, 29522274, 18183640, 24357598, 26178382, 31730495, 31717729, 31370276, 32107864, 33482836, 32427313, 31785789, 25966637, 25370043) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 15, 2019	This variant has been reported in multiple individuals and families with a distinctive presentation of mild NF1 overlapping with features of Noonan syndrome in the published literature (PMID: 26178382 (2015), 25966637 (2015), 25370043 (2015), 24357598 (2014), 19120036 (2009), 18183640 (2007), 12807981 (2003)). The variant has been reported to occur de novo (PMID: 28135719 (2017)). Analysis of this variant using bioinformatics tools (e.g. MutationTaster and PolyPhen-2) for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. -

Neurofibromatosis-Noonan syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Apr 27, 2021	PS4, PP2, PP3, PM2, PS3_Moderate, PM5, PM6 -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurofibromatosis-Noonan syndrome (MIM#601321). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301288). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated pleckstrin homology domain (PMID: 26178382). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Four alternative changes at this residue have been reported in over ten individuals with neurofibromatosis (PMID: 26178382). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is a well-reported pathogenic variant known to cause neurofibromatosis and neurofibromatosis-Noonan syndrome (ClinVar, PMID: 26178382). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic in similarly affected unrelated individuals (PMID:22729224,26520804, 28502725, 29522274 PS4). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Arg1830Ser, p.Arg1830Gly, and p.Arg1830Leu) has been reported as pathogenic (PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.919, 3Cnet: 0.980, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	NF1 NM_000267.3 exon 37 p.Arg1809Cys (c.5425C>T): This variant has been reported in the literature in several individuals with multiple cafe-au-lait spots, some who also presented with features consistent with Noonan syndrome (such as dysmorphic facies and mild intellectual disability), but none with neurofibromas or typical osseous lesions consistent with NF1 (Ekvall 2014 PMID:24357598, Xu 2014 PMID:24789688, Fitzgerald 2015 PMID:25533962, Pinna 2015 PMID:25370043, Rojneuangnit 2015 PMID:26178382, Santoro 2015 PMID:25966637). Therefore, this variant is suggested to be associated with a mild/atypical neurofibromatosis phenotype. This variant has also been reported multiple times in the LOVD NF1 database (https://databases.lovd.nl/shared/genes/NF1). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:208853). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have demonstrated decreased GTP-RAS levels with this variant (Wallis 2018 PMID:29522274). However, these studies may not accurately represent in vivo biological function. Several additional variants at the same amino acid residue (Arg1809Gly, Arg1809Ser, Arg1809Pro, Arg1809Leu) have been reported in individuals with mild neurofibromatosis type 1, further supporting the functional relevance of this codon. In summary, this variant is classified as pathogenic based on the data above. -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 01, 2019

The NF1 c.5488C>T;p.Arg1830Cys variant (also known as c.5425C>T;p.Arg1809Cys) is published in the medical literature in multiple individuals and families with neurofibromatosis type-1, described as mild or atypical as many do not exhibit Lisch nodules and no individuals were described with cutaneous or plexiform neurofibromas, NF1 osseous lesions or symptomatic optic gliomas (Ekvall 2014, Pinna 2015, Rojnueagnit 2015, Santoro 2015). Additionally, other variants in this codon are also associated with a mild or atypical NF1 (Rojnueagnit 2015, Santoro 2015). The c.5488C>T variant is listed in the ClinVar database (Variation ID: 208853) and the dbSNP variant database (rs797045139), but is not listed in the general population-based databases (Exome Variant Server, Genome Aggregation Database). The arginine at this position is well conserved across species and computational algorithms (AlignGVGD, PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as pathogenic and predicted to produce an atypical phenotype. References: Ekvall S et al. Novel association of neurofibromatosis type 1-causing mutations in families with neurofibromatosis-Noonan syndrome. Am J Med Genet A. 2014 Mar;164A(3):579-87. Pinna V et al. p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas. Eur J Hum Genet. 2015 Aug;23(8):1068-71. Rojnueangnit K et al. High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation. Hum Mutat. 2015 Nov;36(11):1052-63. Santoro C et al. Arg(1809) substitution in neurofibromin: further evidence of a genotype-phenotype correlation in neurofibromatosis type 1. Eur J Hum Genet. 2015 Nov;23(11):1460-1. -

Neurodevelopmental delay

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

- -

NF1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2023

The NF1 c.5488C>T variant is predicted to result in the amino acid substitution p.Arg1830Cys. This variant has been well documented to be causative for NF1-related disorders in both de novo and familial cases (alternate nomenclature p.Arg1809Cys; Rojnueangnit et al. 2015. PubMed ID: 26178382; Ekvall et al. 2014. PubMed ID: 24357598; Bianchessi et al. 2015. PubMed ID: 26740943; Santoro et al. 2015. PubMed ID: 25966637; Pinna et al. 2015. PubMed ID: 25370043). Functional studies and familial segregation data both support its pathogenicity (Wallis et al. 2018. PubMed ID: 29522274; Long et al. 2022. PubMed ID: 34694046; Rojnueangnit et al. 2015. PubMed ID: 26178382). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant has been interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/208853/). This variant is interpreted as pathogenic. -

Juvenile myelomonocytic leukemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 03, 2024

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2021

The p.R1809C pathogenic mutation (also known as c.5425C>T), located in coding exon 37 of the NF1 gene, results from a C to T substitution at nucleotide position 5425. The arginine at codon 1809 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was detected in an individual with sporadic neurofibromatosis type 1 (NF1), but was reported to be also observed in unaffected relatives (Ars E et al. J. Med. Genet. 2003; 40:e82). However, a recent study has re-evaluated the family and confirmed that all members with this alteration were affected (Rojnueangnit K et al. Hum. Mutat. 2015 Nov;36:1052-63). This alteration was then described in another proband with features of Noonan/NF1 harboring both this variant and a de novo PTPN11 alteration. Several members of the family were affected with cafe-au-lait spots, but the NF1 variant did not segregate with this feature (Nyström AM et al. Acta Paediatr. 2009; 98:693-8). Moreover, this alteration has also been reported in multiple families exhibiting mild forms of NF1, and to either occur de novo or segregate with the disease in a few cases (Ekvall S et al. Am. J. Med. Genet. A 2014; 164:579-87; Pinna V et al. Eur. J. Hum. Genet. 2015 Aug;23:1068-71; Santoro C et al. Eur. J. Hum. Genet. 2015 Nov;23:1460-1; Bianchessi D et al. Mol Genet Genomic Med. 2015 Nov;3:513-25; Rojnueangnit K et al. Hum. Mutat. 2015 Nov;36:1052-63). In two studies, authors described a unique phenotype seen in individuals with alterations located at p.R1809 consisting of: cafe au lait spots, skinfold freckling, Noonan-like features, and developmental delays, but not cutaneous or plexiform neurofibromas lisch nodules, osseous lesions or symptomatic optic gliomas (Shofty B et al. Semin Pediatr Neurol. 2015 Dec;22:234-9; Rojnueangnit K et al. Hum. Mutat. 2015 Nov;36:1052-63). This alteration was also detected on whole-exome sequencing n a pediatric patient with multiple cafe-au-lait spots, acanthosis nigricans, action tremor, facial palsy, degeneration of anterior horn cells, atrophy/degeneration involving motor neurons, and progressive muscle weakness (Deciphering Developmental Disorders Study. Nature. 2015 Mar;519:223-8). Based on the available evidence, p.R1809C is classified as a pathogenic mutation. -

Intellectual disability

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Apr 20, 2020

- -

Neurofibromatosis, type 1;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Jun 26, 2019

NF1 NM_000267.3 exon 37 p.Arg1809Cys (c.5425C>T): This variant has been reported in the literature in several individuals with multiple cafe-au-lait spots, some who also presented with features consistent with Noonan syndrome (such as dysmorphic facies and mild intellectual disability), but none with neurofibromas or typical osseous lesions consistent with NF1 (Ekvall 2014 PMID:24357598, Xu 2014 PMID:24789688, Fitzgerald 2015 PMID:25533962, Pinna 2015 PMID:25370043, Rojneuangnit 2015 PMID:26178382, Santoro 2015 PMID:25966637). Therefore, this variant is suggested to be associated with a mild/atypical neurofibromatosis phenotype. This variant has also been reported multiple times in the LOVD NF1 database (https://databases.lovd.nl/shared/genes/NF1). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:208853). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have demonstrated decreased GTP-RAS levels with this variant (Wallis 2018 PMID:29522274). However, these studies may not accurately represent in vivo biological function. Several additional variants at the same amino acid residue (Arg1809Gly, Arg1809Ser, Arg1809Pro, Arg1809Leu) have been reported in individuals with mild neurofibromatosis type 1, further supporting the functional relevance of this codon. In summary, this variant is classified as pathogenic based on the data above. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;.;D;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-7.2

D;D;D;.

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;.

Polyphen

1.0

D;D;.;.

Vest4

0.99

MutPred

0.95

Loss of disorder (P = 0.0391);.;.;.;

MVP

1.0

MPC

2.6

ClinPred

1.0

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over