rs1555610893

chr17-31200512-CTG-C

Variant summary

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

The NM_001042492.3(NF1):c.983_984del(p.Cys328Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L327L) 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:6
• Conservation: PhyloP100: 7.37

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 17-31200512-CTG-C is Pathogenic according to our data. Variant chr17-31200512-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 457880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31200512-CTG-C is described in Lovd as [Pathogenic]. Variant chr17-31200512-CTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.983_984del	p.Cys328Ter	frameshift_variant	9/58	ENST00000358273.9
NF1	NM_000267.3	c.983_984del	p.Cys328Ter	frameshift_variant	9/57
NF1	NM_001128147.3	c.983_984del	p.Cys328Ter	frameshift_variant	9/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.983_984del	p.Cys328Ter	frameshift_variant	9/58	1	NM_001042492.3	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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 15, 2022	Variant summary: NF1 c.983_984delGT (p.Cys328X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251436 control chromosomes (gnomAD). c.983_984delGT has been reported in the literature in individuals affected with Neurofibromatosis Type 1 (example: Abernathy_1997, Pros_2008, Thomas_2012, and Sabbagh_2013). These data indicate that the variant is likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 26, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 457880). This variant is also known as 982delGT. This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 9195229, 18546366, 22155606). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys328*) 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). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 17, 2020

The NF1 c.983_984delGT; p.Cys328Ter variant (rs1555610893) is reported in the literature in several individuals affected with neurofibromatosis type 1 (Laycock-van Spyk 2011, Pros 2008). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant deletes two nucleotides induces an early termination codon, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Laycock-van Spyk S et al. Neurofibromatosis type 1-associated tumours: their somatic mutational spectrum and pathogenesis. Hum Genomics. 2011 Oct;5(6):623-90. Pros E et al. Nature and mRNA effect of 282 different NF1 point mutations: focus on splicing alterations. Hum Mutat. 2008 Sep;29(9):E173-93. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 06, 2021

The c.983_984delGT pathogenic mutation, located in coding exon 9 of the NF1 gene, results from a deletion of two nucleotides at nucleotide positions 983 to 984, causing a translational frameshift with a predicted alternate stop codon (p.C328*). This alteration has been seen in multiple individuals meeting clinical diagnosis criteria for Neurofibromatosis type 1 (Abernathy CR et al. Hum Mutat, 1997;9:548-54; Pros E et al. Hum Mutat, 2008 Sep;29:E173-93; Laycock-van Spyk S et al. Hum Genomics, 2011 Oct;5:623-90; Ambry Internal data). This alteration was observed with an allele frequency of 0.00014 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.0000 in 11,241 female controls of Japanese ancestry. In addition, it was observed with an allele frequency of 0.0000 in 53 unselected male breast cancer patients and was observed with an allele frequency of 0.0003 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). Of note, this alteration is also designated as 982delGT in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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)		0.0		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: rs1555610893; hg19: chr17-29527530;