rs771820789

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_001042492.3(NF1):c.2709G>A(p.Val903Val) variant causes a synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V903V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NF1
NM_001042492.3 synonymous

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 4.09

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

neurofibromatosis type 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
neurofibromatosis-Noonan syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
Moyamoya disease
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary pheochromocytoma-paraganglioma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

NF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 17-31229324-G-A is Pathogenic according to our data. Variant chr17-31229324-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 373958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.2709G>A	p.Val903Val	synonymous_variant	Exon 21 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4 link	c.2709G>A	p.Val903Val	synonymous_variant	Exon 21 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.2709G>A	p.Val903Val	synonymous_variant	Exon 21 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461618

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727126

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111806

Other (OTH)

AF:

0.00

AC:

AN:

60374

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Pathogenic:5

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects codon 903 of the NF1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NF1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 48 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with neurofibromatosis type 1 (NF1) (PMID: 17311297, 18041031, 25074460, 29449315, 29618358). ClinVar contains an entry for this variant (Variation ID: 373958). Studies have shown that this variant results in the activation of a cryptic splice site in exon 21 (PMID: 17311297, 18041031; internal data). For these reasons, this variant has been classified as Pathogenic.

Feb 03, 2018

Carson lab, Ohio State University Comprehensive Cancer Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

A female patient met NIH clinical criteria for diagnosis of NF1 including a) axillary and groin freckling; b) >12 neurofibromas, of which one was verified by pathology on biopsy; c) family history of cafe au lait spots. She developed metaplastic breast cancer with somatic loss of heterozygosity of the wildtype allele at this variant position in the NF1 gene. Although this variant at c.2709[G>A] is synonymous, it has been reported previously to introduce a cryptic splice donor site, thereby resulting in deletion of downstream codons and putative changes in neurofibromin protein expression and function.

Feb 15, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Mar 15, 2022

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 08, 2024

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Synonymous variant: previously reported to result in an inframe deletion (PMID: 18041031). In silico tools predict the variant to alter splicing and produce an abnormal transcript [SpliceAI: 0.62 (spliceogenicity >=0.2, non-spliceogenicity <0.1)]. Synonymous variant: previously reported to result in an inframe deletion (PMID: 18041031). Therefore, this variant is classified as Pathogenic (PVS1_M, PS4_S, PM2_M, PP5_S) according to the recommendation of ACMG/AMP guideline.

not provided

Pathogenic:1

Jun 11, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: causes abnormal splicing resulting in in-frame loss of a portion of the protein (PMID: 18041031, 17311297); This variant is associated with the following publications: (PMID: 29618358, 25074460, 32392612, 17311297, 18041031, 29449315, 35626031, 25486365, 2121369)

Juvenile myelomonocytic leukemia

Pathogenic:1

Feb 14, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Pathogenic:1

Dec 31, 2014

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2709G>Apathogenic mutation (also known as p.V903V) located in coding exon 21, results from a G to A substitution at nucleotide position 2709 of the NF1 gene. This nucleotide substitution does not change the encodedamino acid at codon 903. This nucleotide position is not well conservedin available vertebrate species. Both of the two in silico splice site prediction tools, FruitFly andESEfinder,predictthe creation of a new alternate splice donor site.This mutationwas seen in twoindividuals who met NIH clinical criteria for NF1andmRNA studies in both showed that this nucleotide substitutionresultedin an alternatesplice donor site and consequentskipping ofthe last 144 nucleotides of exon 21at the cDNAlevel (Wimmer K, et al. Hum. Mutat. 2007;28(6):599-612;Brinckmann A, et al. Electrophoresis 2007;28(23):4295-301).Based on the supporting evidence, c.2709G>Ais interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.62

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.62

Position offset: -3

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over