rs2274498

Positions:

• chr1-156873862-G-A
• chr1-156873862-G-C
• chr1-156873862-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002529.4(NTRK1):​c.1080G>A​(p.Thr360=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,603,020 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T360T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (32 hom.)
• Consequence: NTRK1 NM_002529.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.81

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 1-156873862-G-A is Benign according to our data. Variant chr1-156873862-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 292883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.81 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00139 (212/152244) while in subpopulation EAS AF= 0.0357 (185/5182). AF 95% confidence interval is 0.0315. There are 6 homozygotes in gnomad4. There are 123 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTRK1	NM_002529.4	c.1080G>A	p.Thr360=	synonymous_variant	8/17	ENST00000524377.7
NTRK1	NM_001012331.2	c.1080G>A	p.Thr360=	synonymous_variant	8/16
NTRK1	NM_001007792.1	c.990G>A	p.Thr330=	synonymous_variant	9/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTRK1	ENST00000524377.7	c.1080G>A	p.Thr360=	synonymous_variant	8/17	1	NM_002529.4	P4

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 212 AN: 152126 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.0356

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000961

GnomAD3 exomes AF: 0.00319 AC: 731 AN: 228972 Hom.: 12 AF XY: 0.00301 AC XY: 373 AN XY: 124100

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000305

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.0372

Gnomad SAS exome AF: 0.00188

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000686

Gnomad OTH exome AF: 0.00211

GnomAD4 exome AF: 0.00109 AC: 1585 AN: 1450776 Hom.: 32 Cov.: 32 AF XY: 0.00113 AC XY: 811 AN XY: 720746

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.0000460

Gnomad4 ASJ exome AF: 0.00108

Gnomad4 EAS exome AF: 0.0317

Gnomad4 SAS exome AF: 0.00170

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.0000840

Gnomad4 OTH exome AF: 0.00125

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152244 Hom.: 6 Cov.: 31 AF XY: 0.00165 AC XY: 123 AN XY: 74438

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.0357

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.000277 Hom.: 0

Bravo AF: 0.00183

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis Benign:5

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.5
DANN	Benign	0.90

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: rs2274498; hg19: chr1-156843654; COSMIC: COSV62327218; COSMIC: COSV62327218;