rs137854556

chr17-31235729-G-Achr17-31235729-G-Cchr17-31235729-G-T

Variant summary

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

The NM_001042492.3(NF1):c.3827G>A(p.Arg1276Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging 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. R1276G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:20O:2

Conservation

PhyloP100: 9.34

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 0 benign, 17 uncertain in NM_001042492.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-31235728-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant where missense usually causes diseases, NF1

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 17-31235729-G-A is Pathogenic according to our data. Variant chr17-31235729-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 68341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31235729-G-A is described in Lovd as [Pathogenic]. Variant chr17-31235729-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3 linkuse as main transcript	c.3827G>A	p.Arg1276Gln	missense_variant	28/58	ENST00000358273.9
NF1	NM_000267.3 linkuse as main transcript	c.3827G>A	p.Arg1276Gln	missense_variant	28/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9 linkuse as main transcript	c.3827G>A	p.Arg1276Gln	missense_variant	28/58	1	NM_001042492.3	P1	P21359-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152152

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251200

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461808

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727206

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74334

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:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:8Other:1

Likely 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	Mar 07, 2022	Published functional studies demonstrate a damaging effect: R1276Q reduces or abolishes Ras activity in vitro (Thomas et al., 2012; Wallis et al., 2018); 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: 32107864, 24951259, 16479075, 27135912, 12522551, 23906300, 22807134, 23047742, 24803665, 22155606, 17311297, 15060124, 21142935, 27322474, 10712197, 27838393, 26607044, 29522274, 29804243, 31595648, 19221814, 23668869, 15863657, 23758643, 31776437, 25486365) -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 29, 2017	The NF1 c.3827G>A, p.Arg1276Gln variant (rs137854556) is a recurrent alteration in individuals diagnosed with neurofibromatosis type I (Ben-Shachar 2013, Fahsold 2000, Jeong 2006, Mattocks 2004, Nemethova 2013, LOVD NF1 database). Functional characterization of the variant protein indicates a significant impairment in activating the catalysis of GTP bound to RAS proteins, resulting in an elevated level of activated RAS kinase (Ahmadian 1997, Thomas 2012). Other missense variants at this position, p.Arg1276Gly and p.Arg1276Pro, have also been implicated in neurofibromatosis type I (Fahsold 2000, Mattocks 2004). The p.Arg1276Gln variant is listed as pathogenic in ClinVar (Variation ID: 68341), and is observed once in the Genome Aggregation Database general population database (1/245936 alleles). The arginine at residue 1276 is highly conserved, and is the catalytic residue for the GAP-related domain of NF1. Computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the missense variant has an impact on the protein structure or function, consistent with the functional studies. Based on the above information, the p.Arg1276Gln variant is classified as pathogenic. References: LOVD NF1 database: https://grenada.lumc.nl/LOVD2/mendelian_genes/home.php?select_db=NF1 Ahmadian M et al. Confirmation of the arginine-finger hypothesis for the GAP-stimulated GTP-hydrolysis reaction of Ras. Nat Struct Biol. 1997; 4(9):686-9. Ben-Shachar S et al. Increased rate of missense/in-frame mutations in individuals with NF1-related pulmonary stenosis: a novel genotype-phenotype correlation. Eur J Hum Genet. 2013; 21(5):535-9. Fahsold R et al. Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet. 2000; 66(3):790-818. Jeong S et al. The spectrum of NF1 mutations in Korean patients with neurofibromatosis type 1. J Korean Med Sci. 2006; 21(1):107-12. Mattocks C et al. Automated comparative sequence analysis identifies mutations in 89 percent of NF1 patients and confirms a mutation cluster in exons 11-17 distinct from the GAP related domain. J Med Genet. 2004; 41(4):e48. Nemethova M et al. Thirty-nine novel neurofibromatosis 1 (NF1) gene mutations identified in Slovak patients. Ann Hum Genet. 2013; 77(5):364-79. Thomas L et al. Assessment of the potential pathogenicity of missense mutations identified in the GTPase-activating protein (GAP)-related domain of the neurofibromatosis type-1 (NF1) gene. Hum Mutat. 2012; 33(12):1687-96. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 18, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2019	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 10, 2022	PP4, PM1, PM2, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 22, 2016	- -

Neurofibromatosis, type 1

Pathogenic:7Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
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	Medical Genomics Laboratory, Department of Genetics UAB	Jun 05, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068341, PS1_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 10712197, 15060124, 16479075, PS4_S). Different missense changes at the same codon have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000353,VCV000068340,VCV000694608, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.887, 3CNET: 0.976, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
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	Invitae	Jan 09, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1276 of the NF1 protein (p.Arg1276Gln). This variant is present in population databases (rs137854556, gnomAD 0.004%). This missense change has been observed in individuals with neurofibromatosis type 1 (PMID: 10712197, 15060124, 16479075, 19221814, 23668869, 27322474). ClinVar contains an entry for this variant (Variation ID: 68341). 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%. Experimental studies have shown that this missense change affects NF1 function (PMID: 9109662, 22807134). This variant disrupts the p.Arg1276 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9668168, 10712197, 26635368). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital Muenster	Mar 03, 2022	ACMG categories: PS3,PM2,PM7,PP3,PP4,PP5 -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

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 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Nov 22, 2021	NF1 NM_000267.3 exon 28 p.Arg1276Gln (c.3827G>A): This variant has been reported in the literature in at least 8 individuals (Fahsold 2000 PMID:10712197, Mattocks 2004 PMID:15060124, Jeong 2006 PMID:16479075, Ko 2013 PMID:23668869, Nemethova 2013 PMID:23758643, Evans 2016 PMID:27322474). This variant was reported to segregate with disease in at least 2 affected family members (Ko 2013 PMID:23668869, Nemethova 2013 PMID:23758643). This variant was also reported in at least 2 individuals with Watson syndrome (Ben-Shachar 2013 PMID:23047742, Evans 2016 PMID:27322474). This variant is present in 1/15300 African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs137854556). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:68341). Evolutionary conservation and computational predictive tools also suggest that this variant may impact the protein. In addition, functional studies have suggested a disease causing impact of this variant, with increased levels of GTP-bound Ras protein vs. wild type (Thomas 2012 PMID:22807134). Of note, two other variants at this codon (p.Arg1276Gly and p.Arg1276Pro) have been reported in association with disease, supporting that this region has functional significance. In summary, this variant is classified as pathogenic based on the data above. -

Neurofibromatosis, type 1;C0553586:Café-au-lait macules with pulmonary stenosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 29, 2016

The p.Arg1276Gln variant in NF1 has been reported in >15 individuals with Neurof ibromatosis type 1 (NF1) (Fahsold 2000, Mattocks 2004, Jeong 2006, Thomas 2012, Nemethova 2013, Mendelian Genes LOVD), 1 individual with Watson syndrome (Ben-sh achar 2013), and segregated with disease in 2 affected relatives from 2 families (Nemethova 2013, Mendelian Genes LOVD). This variant was also reported to have occurred de novo in three of these individuals (Mendelian Genes LOVD). It was al so absent from large population studies (dbSNP rs137854556). In-vitro functional studies provide some evidence that this variant severely impacts protein functi on (Ahmadian 1997, Thomas 2012). In summary, this variant meets criteria to be c lassified as pathogenic for Neurofibromatosis 1 in an autosomal dominant manner based upon segregation studies, absence from controls, and functional evidence. -

Neurofibromatosis-Noonan syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jul 02, 2020

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine (exon 28). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (GAP, GTPase Activating Domain; PMID: 31595648). (N) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Four different variants in the same codon, resulting in changes to glycine, proline, leucine and glutamic acid, have also been shown to cause neurofibromatosis (PMID: 31595648; ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This is a recurrent variant that has been previously reported as pathogenic in multiple patients with neurofibromatosis (ClinVar). Reports also suggest that this variant and other changes affecting the same residue are also associated to a distinct phenotype with Noonan-like features (PMID: 31595648). (P) 1206 - Variant is paternally inherited. However, a child can be more or less severly affected than carrier parent due to variable expressivity (PMID: 20301288). (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2022

The p.R1276Q variant (also known as c.3827G>A), located in coding exon 28 of the NF1 gene, results from a G to A substitution at nucleotide position 3827. The arginine at codon 1276 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in multiple individuals fulfilling diagnostic criteria for neurofibromatosis type 1 (NF1) (Mattocks C et al. J. Med. Genet. 2004 Apr;41:e48; Wimmer K et al. Hum. Mutat. 2007 Jun;28:599-612; Ko JM et al. Pediatr. Neurol. 2013 Jun;48:447-53; Evans DG et al. EBioMedicine 2016 May;7:212-20). This alteration has been shown to impair protein function (Wallis D et al. Hum. Mutat., 2018 06;39:816-821). In addition, this alteration is located in the arginine finger of the GAP-related domain (GRD), which is an essential catalytic element for RasGAP activity (Ambry internal data; Scheffzek K et al. Science, 1997 Jul;277:333-8; Scheffzek K et al. EMBO J., 1998 Aug;17:4313-27; Fahsold R et al. Am. J. Hum. Genet. 2000 Mar;66:790-818; Kiel C et al. Mol. Syst. Biol. 2014 May;10:727). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this variant is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.53

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

D;.;D

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

H;H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.2

D;D;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

1.0

MutPred

0.94

Loss of methylation at R1276 (P = 0.0339);Loss of methylation at R1276 (P = 0.0339);.;

MVP

1.0

MPC

1.8

ClinPred

1.0

GERP RS

6.2

Varity_R

0.96

gMVP

0.83

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