NM_002529.4:c.482G>C

Variant names:

• chr1-156868157-G-C
• NM_002529.4:c.482G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002529.4(NTRK1):​c.482G>C​(p.Arg161Pro) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R161H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.764

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK1	NM_002529.4	c.482G>C	p.Arg161Pro	missense_variant	Exon 5 of 17	ENST00000524377.7	NP_002520.2
NTRK1	NM_001012331.2	c.482G>C	p.Arg161Pro	missense_variant	Exon 5 of 16		NP_001012331.1
NTRK1	NM_001007792.1	c.392G>C	p.Arg131Pro	missense_variant	Exon 6 of 17		NP_001007793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7	c.482G>C	p.Arg161Pro	missense_variant	Exon 5 of 17	1	NM_002529.4	ENSP00000431418.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	.;.;T;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.082
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.76	D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.8	.;L;L;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Uncertain	0.61
Sift	Benign	0.11	T;T;T;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		1.0, 1.0	.;D;D;.
Vest4		0.73
MutPred		0.50		.;Gain of catalytic residue at R161 (P = 0.012);Gain of catalytic residue at R161 (P = 0.012);Gain of catalytic residue at R161 (P = 0.012);
MVP		0.98
MPC		0.67
ClinPred		0.90	D
GERP RS		0.77
Varity_R		0.81
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-156837949; COSMIC: COSV62325803; COSMIC: COSV62325803;