1-156880009-G-C

Variant names:

• chr1-156880009-G-C
• NM_002529.4:c.2057G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_002529.4(NTRK1):​c.2057G>C​(p.Arg686Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R686H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.409

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 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_002529.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK1	NM_002529.4	c.2057G>C	p.Arg686Pro	missense_variant	Exon 16 of 17	ENST00000524377.7	NP_002520.2
NTRK1	NM_001012331.2	c.2039G>C	p.Arg680Pro	missense_variant	Exon 15 of 16		NP_001012331.1
NTRK1	NM_001007792.1	c.1949G>C	p.Arg650Pro	missense_variant	Exon 16 of 17		NP_001007793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7	c.2057G>C	p.Arg686Pro	missense_variant	Exon 16 of 17	1	NM_002529.4	ENSP00000431418.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;.;D;D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	1.5	.;.;L;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.7	D;D;D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.017	D;D;D;D
Sift4G	Uncertain	0.053	T;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.85
MutPred		0.65		.;.;Loss of methylation at R686 (P = 0.0222);.;
MVP		0.92
MPC		1.1
ClinPred		0.96	D
GERP RS		4.2
Varity_R		0.97
gMVP		0.94

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-156849801;