Genetic Variant NM_002529.4:c.2272G>C (chr1-156881523-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. 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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.399

Publications

0 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

hereditary sensory and autonomic neuropathy type 4
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
familial medullary thyroid carcinoma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NTRK1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002529.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NTRK1	NM_002529.4	MANE Select	c.2272G>C	p.Ala758Pro	missense	Exon 17 of 17	NP_002520.2
NTRK1	NM_001012331.2		c.2254G>C	p.Ala752Pro	missense	Exon 16 of 16	NP_001012331.1	P04629-2
NTRK1	NM_001007792.1		c.2164G>C	p.Ala722Pro	missense	Exon 17 of 17	NP_001007793.1	P04629-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NTRK1	ENST00000524377.7	TSL:1 MANE Select	c.2272G>C	p.Ala758Pro	missense	Exon 17 of 17	ENSP00000431418.1	P04629-1
NTRK1	ENST00000368196.7	TSL:1	c.2254G>C	p.Ala752Pro	missense	Exon 16 of 16	ENSP00000357179.3	P04629-2
NTRK1	ENST00000358660.3	TSL:2	c.2263G>C	p.Ala755Pro	missense	Exon 16 of 16	ENSP00000351486.3	J3KP20

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.037

MetaRNN

Uncertain

0.58

MetaSVM

Uncertain

0.34

MutationAssessor

Benign

1.6

PhyloP100

0.40

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.86

REVEL

Uncertain

0.44

Sift

Benign

0.10

Sift4G

Benign

0.14

Polyphen

0.98

Vest4

0.56

MutPred

0.49

Gain of disorder (P = 0.0374)

MVP

0.95

MPC

0.98

ClinPred

0.75

GERP RS

5.0

Varity_R

0.89

gMVP

0.77

Mutation Taster

=58/42

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over