1-26058416-C-T
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_032588.4(TRIM63):c.805G>A(p.Glu269Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00408 in 1,614,160 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_032588.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00301 AC: 458AN: 152168Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00314 AC: 786AN: 250692Hom.: 1 AF XY: 0.00325 AC XY: 441AN XY: 135582
GnomAD4 exome AF: 0.00419 AC: 6129AN: 1461874Hom.: 26 Cov.: 31 AF XY: 0.00406 AC XY: 2956AN XY: 727238
GnomAD4 genome AF: 0.00301 AC: 458AN: 152286Hom.: 1 Cov.: 32 AF XY: 0.00302 AC XY: 225AN XY: 74466
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
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TRIM63: BS1 -
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Hypertrophic cardiomyopathy Uncertain:1
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not specified Benign:1
Variant summary: TRIM63 c.805G>A (p.Glu269Lys) results in a conservative amino acid change located in the COS domain (IPR017903) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0031 in 250692 control chromosomes, predominantly at a frequency of 0.0059 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately one-fold of the estimated maximal expected allele frequency for a pathogenic variant in TRIM63 causing Hypertrophic Cardiomyopathy phenotype (0.005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.805G>A has been reported in the literature in unspecified individuals affected with Hypertrophic Cardiomyopathy as well as in the control cohort, without strong evidence for causality (Chen_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 22821932). ClinVar contains an entry for this variant (Variation ID: 806097). Based on the evidence outlined above, the variant was classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at