rs150271893

Positions:

• chr1-156868157-G-A
• chr1-156868157-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_002529.4(NTRK1):​c.482G>A​(p.Arg161His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000494 in 1,613,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R161C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (0 hom.)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 0.406

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14326906).
• BP6: Variant 1-156868157-G-A is Benign according to our data. Variant chr1-156868157-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 378306.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}. Variant chr1-156868157-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTRK1	NM_002529.4	c.482G>A	p.Arg161His	missense_variant	5/17	ENST00000524377.7
NTRK1	NM_001012331.2	c.482G>A	p.Arg161His	missense_variant	5/16
NTRK1	NM_001007792.1	c.392G>A	p.Arg131His	missense_variant	6/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTRK1	ENST00000524377.7	c.482G>A	p.Arg161His	missense_variant	5/17	1	NM_002529.4	P4

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152252 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000603

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000339 AC: 85 AN: 250506 Hom.: 0 AF XY: 0.000324 AC XY: 44 AN XY: 135634

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000715

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000514 AC: 751 AN: 1461514 Hom.: 0 Cov.: 34 AF XY: 0.000477 AC XY: 347 AN XY: 727090

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000566

Gnomad4 NFE exome AF: 0.000643

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74380

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000773 Hom.: 0

Bravo AF: 0.000446

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000305 AC: 37

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 28, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Reported in patients with neuroblastoma (Lipska et al., 2009); This variant is associated with the following publications: (PMID: 20003389) -

Hereditary insensitivity to pain with anhidrosis Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hereditary cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Benign	0.076
Eigen_PC	Benign	0.039
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.85	D;D;T;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Uncertain	0.12	D
MutationTaster	Benign	0.63	D;D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.11	T;T;T;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.99, 1.0	.;D;D;.
Vest4		0.33
MVP		0.97
MPC		0.30
ClinPred		0.11	T
GERP RS		0.77
Varity_R		0.11
gMVP		0.42

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: rs150271893; hg19: chr1-156837949; COSMIC: COSV105911518; COSMIC: COSV105911518;