17-31350190-T-TAA

Position:

• chr17-31350190-T-TAA

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.7330_7331insAA​(p.Thr2444LysfsTer13) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). 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:2
• Conservation: PhyloP100: 8.44

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 17-31350190-T-TAA is Pathogenic according to our data. Variant chr17-31350190-T-TAA is described in ClinVar as [Pathogenic]. Clinvar id is 504361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.7330_7331insAA	p.Thr2444LysfsTer13	frameshift_variant	50/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.7267_7268insAA	p.Thr2423LysfsTer13	frameshift_variant	49/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.7330_7331insAA	p.Thr2444LysfsTer13	frameshift_variant	50/58	1	NM_001042492.3	ENSP00000351015	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 16, 2018

The c.7267_7268insAA variant in the NF1 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This insertion causes a frameshift starting with codon Threonine 2423, changes this amino acid to a Lysine residue and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Thr2423LysfsX13. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.7267_7268insAA variant is not observed in large population cohorts (Lek et al., 2016). Based on currently available evidence, we consider this a pathogenic variant. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2020

The c.7267_7268insAA pathogenic mutation, located in coding exon 49 of the NF1 gene, results from an insertion of two nucleotides at position 7267, causing a translational frameshift with a predicted alternate stop codon (p.T2423Kfs*13). 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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1064794278; hg19: chr17-29677208;