1-156881523-G-C

Variant names:

• chr1-156881523-G-C
• NM_002529.4:c.2272G>C

Variant summary

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

The NM_002529.4(NTRK1):​c.2272G>C​(p.Ala758Pro) 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. A758T) 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: 0.399

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 domain Protein kinase (size 271) in uniprot entity NTRK1_HUMAN there are 71 pathogenic changes around while only 22 benign (76%) 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.2272G>C	p.Ala758Pro	missense_variant	Exon 17 of 17	ENST00000524377.7	NP_002520.2
NTRK1	NM_001012331.2	c.2254G>C	p.Ala752Pro	missense_variant	Exon 16 of 16		NP_001012331.1
NTRK1	NM_001007792.1	c.2164G>C	p.Ala722Pro	missense_variant	Exon 17 of 17		NP_001007793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7	c.2272G>C	p.Ala758Pro	missense_variant	Exon 17 of 17	1	NM_002529.4	ENSP00000431418.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	.;.;D;D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.6	.;.;L;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.86	N;N;N;N
REVEL	Uncertain	0.44
Sift	Benign	0.10	T;T;T;T
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.98, 1.0	.;D;D;.
Vest4		0.56
MutPred		0.49		.;.;Gain of disorder (P = 0.0374);.;
MVP		0.95
MPC		0.98
ClinPred		0.75	D
GERP RS		5.0
Varity_R		0.89
gMVP		0.77

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: chr1-156851315;