Genetic Variant NM_002529.4:c.2334C>G (chr1-156881585-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_002529.4(NTRK1):c.2334C>G(p.His778Gln) 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. Synonymous variant affecting the same amino acid position (i.e. H778H) 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: -0.121

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_002529.4

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.2334C>G	p.His778Gln	missense	Exon 17 of 17	NP_002520.2
NTRK1	NM_001012331.2		c.2316C>G	p.His772Gln	missense	Exon 16 of 16	NP_001012331.1	P04629-2
NTRK1	NM_001007792.1		c.2226C>G	p.His742Gln	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.2334C>G	p.His778Gln	missense	Exon 17 of 17	ENSP00000431418.1	P04629-1
NTRK1	ENST00000368196.7	TSL:1	c.2316C>G	p.His772Gln	missense	Exon 16 of 16	ENSP00000357179.3	P04629-2
NTRK1	ENST00000358660.3	TSL:2	c.2325C>G	p.His775Gln	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

Benign

0.13

BayesDel_addAF

Benign

-0.019

BayesDel_noAF

Benign

-0.27

CADD

Benign

4.3

(source)

DANN

Benign

0.90

DEOGEN2

Pathogenic

0.81

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.67

M_CAP

Benign

0.048

MetaRNN

Uncertain

0.48

MetaSVM

Uncertain

-0.065

MutationAssessor

Benign

1.1

PhyloP100

-0.12

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-4.7

REVEL

Uncertain

0.39

Sift

Benign

0.066

Sift4G

Benign

0.12

Polyphen

0.67

Vest4

0.35

MutPred

0.51

Gain of MoRF binding (P = 0.0822)

MVP

0.81

MPC

0.70

ClinPred

0.98

GERP RS

-4.0

Varity_R

0.52

gMVP

0.53

Mutation Taster

=53/47

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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