rs587781807

chr17-31226459-AC-Achr17-31226459-AC-ACC

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001042492.3(NF1):c.2033del(p.Pro678ArgfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,454 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T676T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NF1 NM_001042492.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.31

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-31226459-AC-A is Pathogenic according to our data. Variant chr17-31226459-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 428991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31226459-AC-A is described in Lovd as [Pathogenic]. Variant chr17-31226459-AC-A is described in Lovd as [Pathogenic]. Variant chr17-31226459-AC-A is described in Lovd as [Pathogenic]. Variant chr17-31226459-AC-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.2033del	p.Pro678ArgfsTer10	frameshift_variant	18/58	ENST00000358273.9
NF1	NM_000267.3	c.2033del	p.Pro678ArgfsTer10	frameshift_variant	18/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.2033del	p.Pro678ArgfsTer10	frameshift_variant	18/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461454 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727038

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: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual with breast cancer (Palmer et al., 2020); This variant is associated with the following publications: (PMID: 25074460, 14722917, 10712197, 17311297, 22155606, 12522551, 30612635, 32427313) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Neurofibromatosis, type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 21, 2023	This sequence change creates a premature translational stop signal (p.Pro678Argfs*10) 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: 17311297, 21520333; Invitae). ClinVar contains an entry for this variant (Variation ID: 428991). For these reasons, this variant has been classified as Pathogenic. -

Juvenile myelomonocytic leukemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 26, 2023

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 23, 2015

Thec.2033delCpathogenic mutation, located in codingexon18 of theNF1gene, results from a deletion of one nucleotide at position 2033, causing a translationalframeshiftwith a predicted alternate stopcodon. This alteration has previously been identified in individuals with clinical features consistent with neurofibromatosis type 1 (NF1) (Fashold et al. Am. J. Hum. Genet. 2000; 66(3):790-818; Wimmer et al.Hum. Mutat. 2007; 28(6):599-612; Pasmant et al. Eur. J. Hum. Genet. 2014; 23(5):596-601 ).In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alterationis interpreted as a disease-causing mutation (ACMGRecommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587781807; hg19: chr17-29553477;