rs1555614423

chr17-31229852-CA-C

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.2870del(p.Asn957IlefsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. N957N) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.91

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 17-31229852-CA-C is Pathogenic according to our data. Variant chr17-31229852-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 527526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31229852-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.2870del	p.Asn957IlefsTer5	frameshift_variant	22/58	ENST00000358273.9
NF1	NM_000267.3	c.2870del	p.Asn957IlefsTer5	frameshift_variant	22/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.2870del	p.Asn957IlefsTer5	frameshift_variant	22/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2019

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant has been observed in several individuals affected with neurofibromatosis type 1 (PMID: 24922668, Invitae). ClinVar contains an entry for this variant (Variation ID: 527526). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Asn957Ilefs*5) in the NF1 gene. It is expected to result in an absent or disrupted protein product. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 01, 2022

The c.2870delA pathogenic mutation, located in coding exon 22 of the NF1 gene, results from a deletion of one nucleotide at nucleotide position 2870, causing a translational frameshift with a predicted alternate stop codon (p.N957Ifs*5). This mutation has been reported in individuals clinically diagnosed with Neurofibromatosis type 1 (NF1) (Laycock-van Spyk S et al. Hum Genomics, 2011 Oct;5:623-90; Ponti G et al. Anticancer Res, 2014 Jun;34:3021-30). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1555614423; hg19: chr17-29556870;