rs771820789

chr17-31229324-G-Achr17-31229324-G-Cchr17-31229324-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001042492.3(NF1):c.2709G>A(p.Val903=) 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 4.09

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius 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 id is 373958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31229324-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.2709G>A	p.Val903=	synonymous_variant	21/58	ENST00000358273.9
NF1	NM_000267.3	c.2709G>A	p.Val903=	synonymous_variant	21/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.2709G>A	p.Val903=	synonymous_variant	21/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461618 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727126

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 24, 2023	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; Invitae). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Feb 15, 2016	- -
Pathogenic, no assertion criteria provided	research	Carson lab, Ohio State University Comprehensive Cancer Center	Feb 03, 2018	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. -

Juvenile myelomonocytic leukemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 14, 2023

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 21, 2023

Published functional studies demonstrate a damaging effect: causes abnormal splicing resulting in in-frame loss of a portion of the protein (Brinkmann et al., 2007; Wimmer et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29618358, 25074460, 32392612, 17311297, 18041031, 29449315, 25486365, 2121369, 35626031) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2014

The <span style="font-size:13.3333339691162px">c.2709G>Apathogenic mutation (also known as <span style="font-size:13.3333339691162px">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. <span style="font-size:13.3333339691162px">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 <span style="font-size:13.3333339691162px">(Wimmer K, et al. Hum. Mutat. 2007;28(6):599-612;Brinckmann A, et al. Electrophoresis 2007;28(23):4295-301).<span style="font-size:13.3333339691162px">Based on the supporting evidence, <span style="font-size:13.3333339691162px">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	19
Dann	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs771820789; hg19: chr17-29556342;