rs201185829

Positions:

• chr1-156868505-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_002529.4(NTRK1):​c.575G>C​(p.Gly192Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000316 in 1,557,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G192G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: NTRK1 NM_002529.4 missense, splice_region
• Scores: Splicing: ADA: 0.8546
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 1.35

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]

NTRK1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02289632).
• BP6: Variant 1-156868505-G-C is Benign according to our data. Variant chr1-156868505-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 526742.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTRK1	NM_002529.4	c.575G>C	p.Gly192Ala	missense_variant, splice_region_variant	6/17	ENST00000524377.7	NP_002520.2
NTRK1	NM_001012331.2	c.575G>C	p.Gly192Ala	missense_variant, splice_region_variant	6/16		NP_001012331.1
NTRK1	NM_001007792.1	c.485G>C	p.Gly162Ala	missense_variant, splice_region_variant	7/17		NP_001007793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7	c.575G>C	p.Gly192Ala	missense_variant, splice_region_variant	6/17	1	NM_002529.4	ENSP00000431418.1

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000418 AC: 69 AN: 165220 Hom.: 0 AF XY: 0.000434 AC XY: 38 AN XY: 87480

Gnomad AFR exome AF: 0.000317

Gnomad AMR exome AF: 0.000657

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000127

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000320 AC: 450 AN: 1405124 Hom.: 0 Cov.: 33 AF XY: 0.000330 AC XY: 229 AN XY: 693646

Gnomad4 AFR exome AF: 0.0000626

Gnomad4 AMR exome AF: 0.000680

Gnomad4 ASJ exome AF: 0.00329

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000161

Gnomad4 NFE exome AF: 0.000292

Gnomad4 OTH exome AF: 0.000275

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.000390 AC XY: 29 AN XY: 74342

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000528 Hom.: 0

Bravo AF: 0.000348

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000165 AC: 19

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2024	Identified in a cohort of patients with high neuropathy, although individual clinical features or number of patients with this variant were not described (PMID: 27582484); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27582484) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	NTRK1: BP4 -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2021

The p.G192A variant (also known as c.575G>C) is located in coding exon 6 of the NTRK1 gene. The glycine at codon 192 is replaced by alanine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 6. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	.;.;T;T
Eigen	Benign	-0.015
Eigen_PC	Benign	0.041
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.87	D;D;D;D
MetaRNN	Benign	0.023	T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.7	.;L;L;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Uncertain	0.29
Sift	Benign	0.28	T;T;T;T
Sift4G	Benign	0.39	T;T;T;T
Polyphen		0.24, 1.0	.;B;D;.
Vest4		0.44
MVP		0.88
MPC		0.61
ClinPred		0.045	T
GERP RS		3.8
Varity_R		0.15
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.85
dbscSNV1_RF	Pathogenic	0.77
SpliceAI score (max)		0.11		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: rs201185829; hg19: chr1-156838297; COSMIC: COSV62327747; COSMIC: COSV62327747;