rs1555614635

chr17-31230872-G-Achr17-31230872-G-Cchr17-31230872-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001042492.3(NF1):c.3144G>A(p.Trp1048Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.56

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-31230872-G-A is Pathogenic according to our data. Variant chr17-31230872-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 457626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31230872-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.3144G>A	p.Trp1048Ter	stop_gained	24/58	ENST00000358273.9
NF1	NM_000267.3	c.3144G>A	p.Trp1048Ter	stop_gained	24/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.3144G>A	p.Trp1048Ter	stop_gained	24/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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:4

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 28, 2023	The NF1 c.3144G>A variant is classified as Pathogenic (PVS1, PS4_Moderate, PM2) The NF1 c.3144G>A variant is a single nucleotide change in exon 24/58 which is predicted to result in premature termination of the protein product at codon 1048 (PVS1). The variant has been reported in the literature as germline in multiple unrelated patients affected with neurofibromatosis type I and epilepsy (PMID: 23656349, 31776437, 34992632) (PS4_Moderate). This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs1555614635) and in the HGMD database as disease causing (CM143361). It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 457626). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 21, 2023	This sequence change creates a premature translational stop signal (p.Trp1048*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with neurofibromatosis, type 1 (PMID: 21520333, 23656349, 31776437). ClinVar contains an entry for this variant (Variation ID: 457626). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 02, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	40
Dann	Uncertain	0.99
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A
Vest4		0.99
GERP RS		5.5

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

Other links and lift over

dbSNP: rs1555614635; hg19: chr17-29557890; COSMIC: COSV100648000; COSMIC: COSV100648000;