chr1-156879335-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_002529.4(NTRK1):​c.2019G>T​(p.Arg673Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R673R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

NTRK1
NM_002529.4 missense

Scores

10
5
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0640
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a domain Protein kinase (size 271) in uniprot entity NTRK1_HUMAN there are 70 pathogenic changes around while only 22 benign (76%) in NM_002529.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.962

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NTRK1NM_002529.4 linkc.2019G>T p.Arg673Ser missense_variant 15/17 ENST00000524377.7 NP_002520.2 P04629-1
NTRK1NM_001012331.2 linkc.2001G>T p.Arg667Ser missense_variant 14/16 NP_001012331.1 P04629-2X5DR71
NTRK1NM_001007792.1 linkc.1911G>T p.Arg637Ser missense_variant 15/17 NP_001007793.1 P04629-3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NTRK1ENST00000524377.7 linkc.2019G>T p.Arg673Ser missense_variant 15/171 NM_002529.4 ENSP00000431418.1 P04629-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1457538
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
725252
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.27
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.89
.;.;D;D
Eigen
Benign
0.17
Eigen_PC
Benign
0.012
FATHMM_MKL
Benign
0.68
D
LIST_S2
Pathogenic
0.98
D;D;D;D
M_CAP
Uncertain
0.19
D
MetaRNN
Pathogenic
0.96
D;D;D;D
MetaSVM
Uncertain
0.077
D
MutationAssessor
Uncertain
2.5
.;.;M;.
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-5.3
D;D;D;D
REVEL
Pathogenic
0.71
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D
Polyphen
1.0, 0.82
.;D;P;.
Vest4
0.89
MutPred
0.88
.;.;Gain of disorder (P = 0.0465);.;
MVP
0.88
MPC
0.79
ClinPred
1.0
D
GERP RS
-1.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.92
gMVP
0.95

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: chr1-156849127; API