rs1555610854

Positions:

• chr17-31200442-AC-TT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000358273.9(NF1):​c.909_910delinsTT​(p.Arg304Ter) variant causes a stop gained change involving the alteration of a non-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. L303L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 ENST00000358273.9 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.69

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 12 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 17-31200442-AC-TT is Pathogenic according to our data. Variant chr17-31200442-AC-TT is described in ClinVar as [Pathogenic]. Clinvar id is 527594.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.909_910delinsTT	p.Arg304Ter	stop_gained	9/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.909_910delinsTT	p.Arg304Ter	stop_gained	9/57		NP_000258.1
NF1	NM_001128147.3	c.909_910delinsTT	p.Arg304Ter	stop_gained	9/15		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.909_910delinsTT	p.Arg304Ter	stop_gained	9/58	1	NM_001042492.3	ENSP00000351015	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 10, 2017

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). Experimental studies for the c.910C>T variant have shown that, instead of creating a truncated protein, it causes skipping of exon 9 (also known as exon 7 in the literature). This creates a smaller transcript that lacks these codons and is expressed at a decreased amount when compared to wild-type transcript (PMID: 9463322, 10874316). Experimental studies are not available for the c.909_910delACinsTT variant and it is unclear if it will also result in a similar disruption to mRNA splicing. However, either way, it is expected to result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with NF1-related disease. However, a different variant (c.910C>T) giving rise to the same protein effect observed here (p.Arg304*) has been reported in many individuals affected with neurofibromatosis, type 1 (PMID: 23668869, 16786508, 23913538, 10862084) and has been determined to be Pathogenic. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg304*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555610854; hg19: chr17-29527460; COSMIC: COSV62218454;