rs80356674

Positions:

• chr1-156873600-T-A
• chr1-156873600-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_002529.4(NTRK1):​c.851-33T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,443,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: NTRK1 NM_002529.4 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: -0.559

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-156873600-T-A is Pathogenic according to our data. Variant chr1-156873600-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 21308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156873600-T-A is described in Lovd as [Pathogenic]. Variant chr1-156873600-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTRK1	NM_002529.4	c.851-33T>A		intron_variant		ENST00000524377.7	NP_002520.2
NTRK1	NM_001007792.1	c.761-33T>A		intron_variant			NP_001007793.1
NTRK1	NM_001012331.2	c.851-33T>A		intron_variant			NP_001012331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7	c.851-33T>A		intron_variant		1	NM_002529.4	ENSP00000431418	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000340 AC: 8 AN: 235406 Hom.: 0 AF XY: 0.0000232 AC XY: 3 AN XY: 129462

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000446

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: 0.0000125 AC: 18 AN: 1443816 Hom.: 0 Cov.: 31 AF XY: 0.0000139 AC XY: 10 AN XY: 718650

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000455

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	Common pathogenic variant in Japanese, Korean, and Chinese populations. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Intron variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID: 10982191, PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000340, PM2). The variant was observed in trans with a pathogenic variant (NM_002529.3:c.2020G>T) as compound heterozygous (3billion dataset, PM3).The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 27265460 and 28345382, PP1_M). Patient's phenotype is considered compatible with Insensitivity to pain, congenital, with anhidrosis (3billion dataset, PP4).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change falls in intron 7 of the NTRK1 gene. It does not directly change the encoded amino acid sequence of the NTRK1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs80356674, gnomAD 0.05%). This variant has been observed in individual(s) with congenital insensitivity to pain with anhidrosis (CIPA) (PMID: 10982191, 19618435, 23112235, 27265460, 28345382, 29619836). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as IVS7-33T>A and c.935-33T>A. ClinVar contains an entry for this variant (Variation ID: 21308). Studies have shown that this variant results in retention of 137 nucleotides from intron 7 and introduces a premature termination codon (PMID: 10982191). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2000	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 21, 2014

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 14, 2022

Published functional studies demonstrate a damaging effect (activation of upstream cryptic splice acceptor site resulting in aberrant splicing in vitro and incorporation of an abberant fragment into the mRNA) (Miura et al., 2000); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23112235, 30774415, 34674383, 34938316, 25356970, 28345382, 19618435, 27265460, 29770739, 30201336, 29619836, 31857517, 32219930, 30677517, 33422294, 33748046, 32901917, 10982191) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.0
DANN	Benign	0.85
BranchPoint Hunter		6.0

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: rs80356674; hg19: chr1-156843392;