1-156873822-G-C

Variant names:

• chr1-156873822-G-C
• rs797045060
• NM_002529.4:c.1040G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_002529.4(NTRK1):​c.1040G>C​(p.Arg347Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R347C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.260

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_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain Ig-like C2-type 2 (size 66) in uniprot entity NTRK1_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_002529.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-156873822-G-C is Pathogenic according to our data. Variant chr1-156873822-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 209178.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK1	NM_002529.4	c.1040G>C	p.Arg347Pro	missense_variant	Exon 8 of 17	ENST00000524377.7	NP_002520.2
NTRK1	NM_001012331.2	c.1040G>C	p.Arg347Pro	missense_variant	Exon 8 of 16		NP_001012331.1
NTRK1	NM_001007792.1	c.950G>C	p.Arg317Pro	missense_variant	Exon 9 of 17		NP_001007793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7	c.1040G>C	p.Arg347Pro	missense_variant	Exon 8 of 17	1	NM_002529.4	ENSP00000431418.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis Pathogenic:1

Jun 10, 2014

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Likely pathogenicity based on finding it once in our laboratory in trans with a pathogenic variant [c.360-2A>C] in a 28-year-old female with anhidrosis, neuropathy, orthostatic hypotension, ptosis, hyperextensible joints, multiple fractures -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.0067	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	.;.;D;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.68	D;D;D;D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	.;L;L;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.21	T;T;T;T
Sift4G	Benign	0.23	T;T;T;T
Polyphen		1.0, 1.0	.;D;D;.
Vest4		0.63
MutPred		0.60		.;Gain of glycosylation at R347 (P = 0.0941);Gain of glycosylation at R347 (P = 0.0941);Gain of glycosylation at R347 (P = 0.0941);
MVP		0.86
MPC		1.1
ClinPred		0.87	D
GERP RS		5.3
Varity_R		0.90
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs797045060; hg19: chr1-156843614;