rs201185829

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_002529.4(NTRK1):c.575G>A(p.Gly192Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000285 in 1,405,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. G192A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

NTRK1
NM_002529.4 missense, splice_region

Scores

Splicing: ADA: 0.02176

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.35

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: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
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 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 6 uncertain in NM_002529.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24012196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK1	NM_002529.4 link	c.575G>A	p.Gly192Asp	missense_variant, splice_region_variant	Exon 6 of 17	ENST00000524377.7	NP_002520.2	P04629-1
NTRK1	NM_001012331.2 link	c.575G>A	p.Gly192Asp	missense_variant, splice_region_variant	Exon 6 of 16		NP_001012331.1	P04629-2X5DR71
NTRK1	NM_001007792.1 link	c.485G>A	p.Gly162Asp	missense_variant, splice_region_variant	Exon 7 of 17		NP_001007793.1	P04629-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7 link	c.575G>A	p.Gly192Asp	missense_variant, splice_region_variant	Exon 6 of 17	1	NM_002529.4	ENSP00000431418.1		P04629-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000285

AC:

AN:

1405124

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

693646

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31954

American (AMR)

AF:

0.00

AC:

AN:

36784

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25212

East Asian (EAS)

AF:

0.00

AC:

AN:

36310

South Asian (SAS)

AF:

0.00

AC:

AN:

79648

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49698

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4842

European-Non Finnish (NFE)

AF:

0.00000370

AC:

AN:

1082496

Other (OTH)

AF:

0.00

AC:

AN:

58180

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.28

.;.;T;T

Eigen

Benign

-0.0060

Eigen_PC

Benign

0.051

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.84

T;T;T;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.24

T;T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

0.78

.;N;N;.

PhyloP100

1.4

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.94

N;N;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.96

T;T;T;T

Sift4G

Benign

0.76

T;T;T;T

Polyphen

0.62, 1.0

.;P;D;.

Vest4

0.39

MutPred

0.45

.;Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);

MVP

0.88

MPC

0.35

ClinPred

0.16

GERP RS

3.8

Varity_R

0.21

gMVP

0.71

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.022

dbscSNV1_RF

Benign

0.37

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over