1-156879203-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002529.4(NTRK1):c.1887C>T(p.Ala629=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 1,613,480 control chromosomes in the GnomAD database, including 369,340 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A629A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.53 (25958 hom., cov: 31)
  • Exomes 𝑓: 0.67 (343382 hom.)
• Consequence: NTRK1 NM_002529.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:9
• Conservation: PhyloP100: -3.99

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 1-156879203-C-T is Benign according to our data. Variant chr1-156879203-C-T is described in ClinVar as [Benign]. Clinvar id is 138564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156879203-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.99 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTRK1	NM_002529.4	c.1887C>T	p.Ala629=	synonymous_variant	15/17	ENST00000524377.7
NTRK1	NM_001012331.2	c.1869C>T	p.Ala623=	synonymous_variant	14/16
NTRK1	NM_001007792.1	c.1779C>T	p.Ala593=	synonymous_variant	15/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTRK1	ENST00000524377.7	c.1887C>T	p.Ala629=	synonymous_variant	15/17	1	NM_002529.4	P4

Frequencies

GnomAD3 genomes AF: 0.533 AC: 80948 AN: 151840 Hom.: 25959 Cov.: 31

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.711

Gnomad AMR AF: 0.559

Gnomad ASJ AF: 0.750

Gnomad EAS AF: 0.0503

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.731

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.724

Gnomad OTH AF: 0.556

GnomAD3 exomes AF: 0.578 AC: 143744 AN: 248724 Hom.: 47473 AF XY: 0.582 AC XY: 78382 AN XY: 134652

Gnomad AFR exome AF: 0.198

Gnomad AMR exome AF: 0.575

Gnomad ASJ exome AF: 0.751

Gnomad EAS exome AF: 0.0396

Gnomad SAS exome AF: 0.393

Gnomad FIN exome AF: 0.732

Gnomad NFE exome AF: 0.724

Gnomad OTH exome AF: 0.638

GnomAD4 exome AF: 0.667 AC: 975001 AN: 1461522 Hom.: 343382 Cov.: 70 AF XY: 0.661 AC XY: 480752 AN XY: 727024

Gnomad4 AFR exome AF: 0.193

Gnomad4 AMR exome AF: 0.578

Gnomad4 ASJ exome AF: 0.750

Gnomad4 EAS exome AF: 0.0457

Gnomad4 SAS exome AF: 0.398

Gnomad4 FIN exome AF: 0.733

Gnomad4 NFE exome AF: 0.726

Gnomad4 OTH exome AF: 0.620

GnomAD4 genome AF: 0.533 AC: 80961 AN: 151958 Hom.: 25958 Cov.: 31 AF XY: 0.526 AC XY: 39055 AN XY: 74300

Gnomad4 AFR AF: 0.214

Gnomad4 AMR AF: 0.558

Gnomad4 ASJ AF: 0.750

Gnomad4 EAS AF: 0.0506

Gnomad4 SAS AF: 0.371

Gnomad4 FIN AF: 0.731

Gnomad4 NFE AF: 0.724

Gnomad4 OTH AF: 0.554

Alfa AF: 0.676 Hom.: 40424

Bravo AF: 0.512

Asia WGS AF: 0.233 AC: 812 AN: 3478

EpiCase AF: 0.716

EpiControl AF: 0.717

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1 Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 28, 2017	- -

Hereditary insensitivity to pain with anhidrosis Benign:5

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	3.8
Dann	Benign	0.82

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: rs6337; hg19: chr1-156848995; COSMIC: COSV62325231; COSMIC: COSV62325231;