rs1555613558

Variant names:

• chr17-31225125-CT-C
• NM_001042492.3:c.1882delT

Your query was ambiguous. Multiple possible variants found:

• chr17-31225125-CT-C
• chr17-31225125-CT-CTT

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.1882delT​(p.Tyr628ThrfsTer3) variant causes a frameshift 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. Y628Y) has been classified as 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:3
• Conservation: PhyloP100: 0.460

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 17-31225125-CT-C is Pathogenic according to our data. Variant chr17-31225125-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 1213688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31225125-CT-C is described in Lovd as [Pathogenic]. Variant chr17-31225125-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.1882delT	p.Tyr628ThrfsTer3	frameshift_variant	Exon 17 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.1882delT	p.Tyr628ThrfsTer3	frameshift_variant	Exon 17 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.1882delT	p.Tyr628ThrfsTer3	frameshift_variant	Exon 17 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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1;C0553586:Café-au-lait macules with pulmonary stenosis Pathogenic:1

Sep 23, 2020

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The inherited heterozygous variant (c.1882del, p.Tyr628ThrfsTer3) has been reported in individuals affected with NF1-related disorders [PMID: 24789688; PMID: 30530636]. The variant is absent from gnomAD(v3) database indicating it is an extremely rare allele in the populations represented in this database. This one nucleotide deletion located in exon 17 (of 58) of the NF1 gene alters the wild-type translational reading frame and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Loss of function variants in NF1 are known to be pathogenic. This variant was inherited from a parent who also has symptoms of NF1-related disorder. Based on the available evidence, the inherited c.1882del (p.Tyr628ThrfsTer3) variant in the NF1 gene is assessed as pathogenic. -

Neurofibromatosis, type 1 Pathogenic:1

Aug 07, 2024

Department of Human Genetics, Hannover Medical School

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Oct 31, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.1882del; p.Tyr628ThrfsTer3 variant is reported in the literature in individuals affected with neurofibromatosis type 1 (Frayling 2019, Xu 2014). This variant is also reported in ClinVar (Variation ID: 1213688), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, several downstream truncating variants have been described in individuals with neurofibromatosis type 1 and are considered pathogenic (Frayling 2019, Wu-Chou 2018, Xu 2014). Based on available information, this variant is considered to be pathogenic. References: Frayling IM et al. Breast cancer risk in neurofibromatosis type 1 is a function of the type of NF1 gene mutation: a new genotype-phenotype correlation. J Med Genet. 2019 Apr;56(4):209-219. PMID: 30530636. Wu-Chou YH et al. Genetic diagnosis of neurofibromatosis type 1: targeted next- generation sequencing with Multiple Ligation-Dependent Probe Amplification analysis. J Biomed Sci. 2018 Oct 5;25(1):72. PMID: 30290804. Xu W et al. Fifty-four novel mutations in the NF1 gene and integrated analyses of the mutations that modulate splicing. Int J Mol Med. 2014 Jul;34(1):53-60. PMID: 24789688. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-29552143;