rs1799770

chr1-156879117-CA-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002529.4(NTRK1):c.1806-4del variant causes a splice region, splice polypyrimidine tract, 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. 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, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.73

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 Benign. Variant got -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 [Likely_benign]. Clinvar id is 292891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156879117-CA-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
NTRK1	NM_002529.4	c.1806-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000524377.7
NTRK1	NM_001007792.1	c.1698-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
NTRK1	NM_001012331.2	c.1788-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTRK1	ENST00000524377.7	c.1806-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002529.4	P4

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

GnomAD3 exomes AF: 0.0593 AC: 14732 AN: 248338 Hom.: 602 AF XY: 0.0630 AC XY: 8478 AN XY: 134650

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 SAS exome AF: 0.134

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

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.0323

Gnomad4 ASJ exome AF: 0.0631

Gnomad4 EAS exome AF: 0.0605

Gnomad4 SAS exome AF: 0.138

Gnomad4 FIN exome AF: 0.0263

Gnomad4 NFE exome AF: 0.0453

Gnomad4 OTH exome AF: 0.0601

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

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.0581

Gnomad4 ASJ AF: 0.0619

Gnomad4 EAS AF: 0.0763

Gnomad4 SAS AF: 0.129

Gnomad4 FIN AF: 0.0252

Gnomad4 NFE AF: 0.0438

Gnomad4 OTH AF: 0.0592

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

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2018	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2019

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

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

Publications

LitVar

Other links and lift over

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