rs398122810

Variant names:

• chr1-156861140-CTG-C
• rs398122810
• NM_002529.4:c.207_208delTG

Variant summary

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

The NM_002529.4(NTRK1):​c.207_208delTG​(p.Glu70AlafsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000254 in 1,575,182 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: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NTRK1 NM_002529.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.98

Genes affected

NTRK1 (HGNC:8031): (neurotrophic receptor tyrosine kinase 1) This gene encodes a member of the neurotrophic tyrosine kinase receptor (NTKR) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. The presence of this kinase leads to cell differentiation and may play a role in specifying sensory neuron subtypes. Mutations in this gene have been associated with congenital insensitivity to pain, anhidrosis, self-mutilating behavior, cognitive disability and cancer. Alternate transcriptional splice variants of this gene have been found, but only three have been characterized to date. [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 1-156861140-CTG-C is Pathogenic according to our data. Variant chr1-156861140-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 29920.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-156861140-CTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK1	NM_002529.4	c.207_208delTG	p.Glu70AlafsTer16	frameshift_variant	Exon 1 of 17	ENST00000524377.7	NP_002520.2
NTRK1	NM_001012331.2	c.207_208delTG	p.Glu70AlafsTer16	frameshift_variant	Exon 1 of 16		NP_001012331.1
NTRK1	NM_001007792.1	c.123-3213_123-3212delTG		intron_variant	Intron 2 of 16		NP_001007793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7	c.207_208delTG	p.Glu70AlafsTer16	frameshift_variant	Exon 1 of 17	1	NM_002529.4	ENSP00000431418.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1422928 Hom.: 0 AF XY: 0.00000283 AC XY: 2 AN XY: 705522

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: 0.00000274

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74380

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis Pathogenic:2

Mar 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu70Alafs*16) in the NTRK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NTRK1 are known to be pathogenic (PMID: 10982191). This variant is present in population databases (rs398122810, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with congenital insensitivity to pain and anhidrosis (PMID: 19250380). It has also been observed to segregate with disease in related individuals. This variant is also known as c.207-208 delTG. ClinVar contains an entry for this variant (Variation ID: 29920). For these reasons, this variant has been classified as Pathogenic. -

Mar 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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: rs398122810; hg19: chr1-156830932;