rs62640939

chr1-156881523-G-Achr1-156881523-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002529.4(NTRK1):c.2272G>A(p.Ala758Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000954 in 1,601,278 control chromosomes in the GnomAD database, including 12 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. A758A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0053 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (6 hom.)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.399

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 -18 ACMG points.

• PM1: In a domain Protein kinase (size 271) in uniprot entity NTRK1_HUMAN there are 69 pathogenic changes around while only 22 benign (76%) in NM_002529.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.007014364).
• BP6: Variant 1-156881523-G-A is Benign according to our data. Variant chr1-156881523-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 386229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00526 (801/152296) while in subpopulation AFR AF= 0.0187 (778/41558). AF 95% confidence interval is 0.0176. There are 6 homozygotes in gnomad4. There are 402 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTRK1	NM_002529.4	c.2272G>A	p.Ala758Thr	missense_variant	17/17	ENST00000524377.7
NTRK1	NM_001012331.2	c.2254G>A	p.Ala752Thr	missense_variant	16/16
NTRK1	NM_001007792.1	c.2164G>A	p.Ala722Thr	missense_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTRK1	ENST00000524377.7	c.2272G>A	p.Ala758Thr	missense_variant	17/17	1	NM_002529.4	P4

Frequencies

GnomAD3 genomes AF: 0.00526 AC: 800 AN: 152178 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

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: 0.00191

GnomAD3 exomes AF: 0.00119 AC: 268 AN: 224318 Hom.: 1 AF XY: 0.000871 AC XY: 106 AN XY: 121638

Gnomad AFR exome AF: 0.0172

Gnomad AMR exome AF: 0.000744

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000107

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000200

Gnomad OTH exome AF: 0.000359

GnomAD4 exome AF: 0.000502 AC: 727 AN: 1448982 Hom.: 6 Cov.: 31 AF XY: 0.000422 AC XY: 304 AN XY: 719716

Gnomad4 AFR exome AF: 0.0186

Gnomad4 AMR exome AF: 0.000908

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000952

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000542

Gnomad4 OTH exome AF: 0.000902

GnomAD4 genome AF: 0.00526 AC: 801 AN: 152296 Hom.: 6 Cov.: 32 AF XY: 0.00540 AC XY: 402 AN XY: 74468

Gnomad4 AFR AF: 0.0187

Gnomad4 AMR AF: 0.00118

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: 0.00189

Alfa AF: 0.00304 Hom.: 5

Bravo AF: 0.00602

ESP6500AA AF: 0.0171 AC: 75

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00137 AC: 166

Asia WGS AF: 0.000866 AC: 3 AN: 3478

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:6

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 16, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2019	This variant is associated with the following publications: (PMID: 26215504) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 02, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Benign	0.071
Eigen_PC	Benign	0.089
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.85	D;D;D;D
MetaRNN	Benign	0.0070	T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationTaster	Benign	0.57	N;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.70	N;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.15	T;T;T;T
Sift4G	Benign	0.30	T;T;T;T
Polyphen		0.79, 0.99	.;P;D;.
Vest4		0.14
MVP		0.92
MPC		0.28
ClinPred		0.022	T
GERP RS		5.0
Varity_R		0.22
gMVP		0.20

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: rs62640939; hg19: chr1-156851315; COSMIC: COSV99061307;