rs606231467
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_002529.4(NTRK1):c.1550G>A(p.Gly517Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G517G) has been classified as Likely benign.
Frequency
Consequence
NM_002529.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NTRK1 | NM_002529.4 | c.1550G>A | p.Gly517Glu | missense_variant | 13/17 | ENST00000524377.7 | |
NTRK1 | NM_001012331.2 | c.1532G>A | p.Gly511Glu | missense_variant | 12/16 | ||
NTRK1 | NM_001007792.1 | c.1442G>A | p.Gly481Glu | missense_variant | 13/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NTRK1 | ENST00000524377.7 | c.1550G>A | p.Gly517Glu | missense_variant | 13/17 | 1 | NM_002529.4 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251454Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135916
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461894Hom.: 0 Cov.: 34 AF XY: 0.00000963 AC XY: 7AN XY: 727248
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74346
ClinVar
Submissions by phenotype
Hereditary insensitivity to pain with anhidrosis Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 04, 2024 | Variant summary: NTRK1 c.1532G>A (p.Gly511Glu) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251454 control chromosomes. c.1532G>A has been reported in the literature in at-least one individual affected with features of Hereditary Insensitivity To Pain With Anhidrosis (example, Hepburn_2014 cited in Shaikh_2017). At least one publication reports experimental evidence evaluating an impact on protein function (Shaikh_2017). The most pronounced variant effect results in abolished PLC gamma signaling. The following publications have been ascertained in the context of this evaluation (PMID: 25359976, 35471943, 27676246, 30201336). ClinVar contains an entry for this variant (Variation ID: 161443). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 31, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at