rs1553260399

Positions:

• chr1-156861074-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002529.4(NTRK1):​c.140G>C​(p.Gly47Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 3.16

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3799487).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTRK1	NM_002529.4	c.140G>C	p.Gly47Ala	missense_variant	1/17	ENST00000524377.7
NTRK1	NM_001012331.2	c.140G>C	p.Gly47Ala	missense_variant	1/16
NTRK1	NM_001007792.1	c.123-3280G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTRK1	ENST00000524377.7	c.140G>C	p.Gly47Ala	missense_variant	1/17	1	NM_002529.4	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1422002 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 705120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 25, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 04, 2022	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 47 of the NTRK1 protein (p.Gly47Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NTRK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 526732). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NTRK1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	0.0078	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	0.56	D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.66	N;N;N
REVEL	Benign	0.21
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.45	T;T;T
Polyphen		0.98	D;D;.
Vest4		0.33
MutPred		0.20		Loss of glycosylation at S46 (P = 0.0565);Loss of glycosylation at S46 (P = 0.0565);Loss of glycosylation at S46 (P = 0.0565);
MVP		0.88
MPC		0.52
ClinPred		0.55	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.16
gMVP		0.51

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: rs1553260399; hg19: chr1-156830866;