17-31159044-ATCTC-ATC

Position:

• chr17-31159044-ATCTC-ATC

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.246_247del​(p.Gln83ValfsTer23) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,456,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NF1 NM_001042492.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.47

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 17-31159044-ATC-A is Pathogenic according to our data. Variant chr17-31159044-ATC-A is described in ClinVar as [Pathogenic]. Clinvar id is 527470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31159044-ATC-A is described in Lovd as [Pathogenic]. Variant chr17-31159044-ATC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.246_247del	p.Gln83ValfsTer23	frameshift_variant	3/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.246_247del	p.Gln83ValfsTer23	frameshift_variant	3/57		NP_000258.1
NF1	NM_001128147.3	c.246_247del	p.Gln83ValfsTer23	frameshift_variant	3/15		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.246_247del	p.Gln83ValfsTer23	frameshift_variant	3/58	1	NM_001042492.3	ENSP00000351015	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250874 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135674

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456846 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 725072

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 22, 2022	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this premature translational stop signal alters NF1 gene expression (PMID: 25788518). ClinVar contains an entry for this variant (Variation ID: 527470). This variant is also known as c.240_241delTC. This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 16944272, 18546366, 23758643). This variant is present in population databases (rs771115661, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Gln83Valfs*23) 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). -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 21, 2022

The c.246_247delTC pathogenic mutation, located in coding exon 3 of the NF1 gene, results from a deletion of two nucleotides at nucleotide positions 246 to 247, causing a translational frameshift with a predicted alternate stop codon (p.Q83Vfs*23). This alteration was identified in two separate cohorts undergoing genetic testing due to a diagnosis or clinical suspicion of neurofibromatosis type 1 (Pros E et al. Hum Mutat, 2008 Sep;29:E173-93; Bolcekova A et al. Neoplasma, 2013;60:655-65). 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)		0.040		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: rs771115661; hg19: chr17-29486062;