NM_002529.4:c.1806-4delA

Variant names:

• chr1-156879117-CA-C
• rs1799770
• NM_002529.4:c.1806-4delA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002529.4(NTRK1):​c.1806-4delA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0539 in 1,613,498 control chromosomes in the GnomAD database, including 3,040 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (431 hom., cov: 31)
  • Exomes 𝑓: 0.053 (2609 hom.)
• Consequence: NTRK1 NM_002529.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.73
• Publications: 9 publications found

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]

NTRK1 Gene-Disease associations (from GenCC):

• hereditary sensory and autonomic neuropathy type 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• familial medullary thyroid carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 1-156879117-CA-C is Benign according to our data. Variant chr1-156879117-CA-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 292891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK1	NM_002529.4	c.1806-4delA		splice_region_variant, intron_variant	Intron 14 of 16	ENST00000524377.7	NP_002520.2
NTRK1	NM_001012331.2	c.1788-4delA		splice_region_variant, intron_variant	Intron 13 of 15		NP_001012331.1
NTRK1	NM_001007792.1	c.1698-4delA		splice_region_variant, intron_variant	Intron 14 of 16		NP_001007793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7	c.1806-4delA		splice_region_variant, intron_variant	Intron 14 of 16	1	NM_002529.4	ENSP00000431418.1

Frequencies

GnomAD3 genomes AF: 0.0650 AC: 9892 AN: 152080 Hom.: 423 Cov.: 31

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0582

Gnomad ASJ AF: 0.0619

Gnomad EAS AF: 0.0763

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.0252

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0439

Gnomad OTH AF: 0.0599

GnomAD2 exomes AF: 0.0593 AC: 14732 AN: 248338 AF XY: 0.0630

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.0319

Gnomad ASJ exome AF: 0.0605

Gnomad EAS exome AF: 0.0703

Gnomad FIN exome AF: 0.0246

Gnomad NFE exome AF: 0.0445

Gnomad OTH exome AF: 0.0568

GnomAD4 exome AF: 0.0527 AC: 76962 AN: 1461300 Hom.: 2609 Cov.: 30 AF XY: 0.0555 AC XY: 40337 AN XY: 726954

African (AFR) AF: 0.110 AC: 3695 AN: 33466

American (AMR) AF: 0.0323 AC: 1446 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0631 AC: 1649 AN: 26122

East Asian (EAS) AF: 0.0605 AC: 2401 AN: 39700

South Asian (SAS) AF: 0.138 AC: 11861 AN: 86226

European-Finnish (FIN) AF: 0.0263 AC: 1403 AN: 53410

Middle Eastern (MID) AF: 0.0940 AC: 515 AN: 5478

European-Non Finnish (NFE) AF: 0.0453 AC: 50363 AN: 1111844

Other (OTH) AF: 0.0601 AC: 3629 AN: 60340

GnomAD4 genome AF: 0.0652 AC: 9927 AN: 152198 Hom.: 431 Cov.: 31 AF XY: 0.0660 AC XY: 4908 AN XY: 74402

African (AFR) AF: 0.106 AC: 4408 AN: 41510

American (AMR) AF: 0.0581 AC: 889 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0619 AC: 215 AN: 3472

East Asian (EAS) AF: 0.0763 AC: 395 AN: 5178

South Asian (SAS) AF: 0.129 AC: 622 AN: 4806

European-Finnish (FIN) AF: 0.0252 AC: 267 AN: 10610

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0438 AC: 2982 AN: 68012

Other (OTH) AF: 0.0592 AC: 125 AN: 2110

Alfa AF: 0.0306 Hom.: 24

Bravo AF: 0.0669

Asia WGS AF: 0.0810 AC: 284 AN: 3478

EpiCase AF: 0.0504

EpiControl AF: 0.0493

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis Benign:5

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

May 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Aug 30, 2019

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-3.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1799770; hg19: chr1-156848909; COSMIC: COSV62324345; COSMIC: COSV62324345;