rs786202112

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_001042492.3(NF1):c.5609G>A(p.Arg1870Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/25 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1870L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 9.56

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1

In a helix (size 16) in uniprot entity NF1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) 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 chr17-31327839-G-T is described in Lovd as [Pathogenic].

PP2

Missense variant in the NF1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 399 curated pathogenic missense variants (we use a threshold of 10). The gene has 143 curated benign missense variants. Gene score misZ: 6.5427 (above the threshold of 3.09). Trascript score misZ: 8.4054 (above the threshold of 3.09). GenCC associations: The gene is linked to neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

PP5

Variant 17-31327839-G-A is Pathogenic according to our data. Variant chr17-31327839-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 185354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31327839-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.5609G>A	p.Arg1870Gln	missense_variant, splice_region_variant	Exon 38 of 58	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.3 link	c.5546G>A	p.Arg1849Gln	missense_variant, splice_region_variant	Exon 37 of 57		NP_000258.1	P21359-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.5609G>A	p.Arg1870Gln	missense_variant, splice_region_variant	Exon 38 of 58	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461166

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726922

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Pathogenic:8

Oct 26, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Nov 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1849 of the NF1 protein (p.Arg1849Gln). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with neurofibromatosis 1 (NF1) (PMID: 10607834, 10712197, 10862084, 10980545, 11857752, 12807981, 18484666, 18546366, 23668869, 23913538, 24932921, 25325900). ClinVar contains an entry for this variant (Variation ID: 185354). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 37, also known as exon 29, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 10607834, 10980545; internal data). For these reasons, this variant has been classified as Pathogenic. -

Mar 15, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5546G>A;p.(Arg1849Gln) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 185354; PMID: 23668869; 16937374; 10862084; 10980545; 11857752; 12807981; 10607834) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 16937374; 18546366; 10862084; 10980545) - PS3. This variant is not present in population databases (rs786202112, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Missense variant in NF1 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID:. 10607834. Predicted Consequence/Location:). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000185354). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10862084, 10980545, 12807981, 25325900, 29673180, 31776437). A different missense change at the same codon (p.Arg1870Leu) has been reported to be associated with NF1 related disorder (ClinVar ID: VCV001070186). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Jun 14, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: aberrant splicing resulting in transcripts lacking exon 37 or exons 37 and 38, also called exons 29 and 30 using alternate exon numbering (Girodon-Boulandet et al., 2000; Messiaen et al., 2000); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing; This variant is associated with the following publications: (PMID: 16830335, 30014477, 10862084, 29673180, 25325900, 34418705, 23668869, 25403449, 10712197, 27322474, 19292874, 10607834, 24932921, 29489754, 28955729, 28152038, 10980545, 29618358, 31766501, 16937374, 31776437, 33372952, 33877690, 23913538) -

Apr 26, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PS4_moderate, PVS1 -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rhabdomyosarcoma

Pathogenic:1

Sep 01, 2020

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Juvenile myelomonocytic leukemia

Pathogenic:1

Feb 07, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Pathogenic:1

Feb 22, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5546G>A (p.R1849Q) alteration is located in coding exon 37 of the NF1 gene. This alteration results from a G to A substitution at nucleotide position 5546, causing the arginine (R) at amino acid position 1849 to be replaced by a glutamine (Q). This change occurs in the last base pair of coding exon37, which makes it likely to have some effect on normal mRNA splicing. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in multiple individuals with a clinical diagnosis of neurofibromatosis type 1 (Ars, 2000; Rübben, 2006; Ko, 2013; Anastasaki, 2017; Palma Milla, 2018). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. RNA studies have demonstrated that this variant results in skipping of coding exon 37 (Ars, 2000; Pros, 2006; Ambry internal data). In silico splice site analysis predicts that this alteration may weaken the native splice donor site. This amino acid alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Jul 20, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1870Q pathogenic mutation (also known as c.5609G>A) is located in coding exon 38 of the NF1 gene. This pathogenic mutation results from a G to A substitution at nucleotide position 5609. The amino acid change results in an arginine to glutamine at codon 1870, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 38, which makes it likely to have some effect on normal mRNA splicing. This mutation was first described in one familial and two sporadic cases of neurofibromatosis type 1 (NF1). These researchers performed further functional studies and demonstrated a skipping of exon 38, leading to a truncated protein (Ars E, Hum. Mol. Genet. 2000 Jan; 9(2):237-47). This mutation was also identified in two unrelated individuals of Korean descent with NF1 (Ko JM, Pediatr. Neurol. 2013 Jun; 48(6):447-53) as well as in one family of Indonesian descent with NF1 (Rübben A, Mol. Cancer 2006 ; 5():36). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 55000 alleles tested) in our clinical cohort. Based on nucleotide sequence alignment, this position is completely conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native donor splice site, but is predicted to weaken (but not abolish) the efficacy of the native donor splice site by ESEfinder. In the published literature, this alteration is also referred to as c.5546G>A (R1849Q). Based on the available evidence, p.R1870Q is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;.;D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.97

D;D;D;D

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.86

D;D;D;D

MetaSVM

Uncertain

-0.18

MutationAssessor

Pathogenic

3.3

M;.;.;.

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.5

D;D;D;.

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

D;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;.

Polyphen

1.0

D;D;.;.

Vest4

0.98

MVP

0.96

MPC

2.4

ClinPred

1.0

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.75

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.32

Position offset: 0

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