rs863224446

Variant names:

• chr17-31229465-G-A
• rs863224446
• NM_001042492.3:c.2850G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-31229465-G-A
• chr17-31229465-G-C
• chr17-31229465-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001042492.3(NF1):​c.2850G>A​(p.Gln950Gln) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.59

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-31229465-G-A is Pathogenic according to our data. Variant chr17-31229465-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 561684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31229465-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.2850G>A	p.Gln950Gln	splice_region_variant, synonymous_variant	Exon 21 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.2850G>A	p.Gln950Gln	splice_region_variant, 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	c.2850G>A	p.Gln950Gln	splice_region_variant, synonymous_variant	Exon 21 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:2

Aug 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 950 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 may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of neurofibromatosis type I (PMID: 21520333, 26740943, 31717729). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 561684). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in r.2618_2850del, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 26740943; Invitae). 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

- -

not provided Pathogenic:1

Nov 01, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Exonic splice site variant demonstrated to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (PMID: 26740943); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31717729, 31766501, 26740943) -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1

Aug 25, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2850G>A pathogenic mutation (also known as p.Q950Q), located in coding exon 21 of the NF1 gene, results from a G to A substitution at nucleotide position 2850. This nucleotide substitution does not change the glutamine at codon 950. However, this change occurs in the last base pair of coding exon 21, which makes it likely to have some effect on normal mRNA splicing. This mutation has been detected in multiple individuals with a clinical or suspected diagnosis of neurofibromatosis type 1 (NF1); it occurred de novo in one of the individuals (Bianchessi D et al. Mol Genet Genomic Med, 2015 Nov;3:513-25; Melloni G et al. Cancers (Basel), 2019 11;11:; Yao R et al. Genes (Basel), 2019 10;10:; Ambry internal data). In addition, this alteration results in the deletion of 233 nucleotides, leading to a frameshift in the NF1 protein (Bianchessi D et al. Mol Genet Genomic Med, 2015 Nov;3:513-25; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.66		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs863224446; hg19: chr17-29556483; COSMIC: COSV62209219; COSMIC: COSV62209219;