chr15-63048582-G-A
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2
The NM_001407340.1(TPM1):c.7G>A(p.Gly3Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000379 in 1,528,492 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001407340.1 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152210Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000719 AC: 9AN: 125154Hom.: 0 AF XY: 0.0000583 AC XY: 4AN XY: 68656
GnomAD4 exome AF: 0.0000371 AC: 51AN: 1376170Hom.: 0 Cov.: 34 AF XY: 0.0000457 AC XY: 31AN XY: 678786
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152322Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4AN XY: 74492
ClinVar
Submissions by phenotype
not specified Uncertain:1
proposed classification - variant undergoing re-assessment, contact laboratory -
Long QT syndrome;C0340493:Paroxysmal familial ventricular fibrillation Benign:1
The TPM1 Gly3Arg variant has been identified previously in 1 (heterozygous) proband with left ventricular dilation, wall thinning (LMM, Pers. Comm). It has also been identified in 1 Saudi Arabian family with 2 children affected with DCM and 1 child affected with Patent Ductus Arteruisus, all 3 children were found to be homozygous for p.Gly3Arg, the heterozygous parents were not affected (Al Harbi K, et al., 2016). We identified this variant in 2 heterozygous probands, The first was diagnosed with Long QT. The second was diagnosed with idiopathic ventricular fibrillation, and has a family history of sudden death. The variant is found in Genome Aggregation Database (MAF=0.00007917, http://gnomad.broadinstitute.org/), and the Greater Middle Eastern variome project (MAF= 0.00304, http://igm.ucsd.edu/gme/) which is higher then expected for a genetic heart condition. In silico tools PolyPhen-2 and MutationTaster predict this variant to be benign, however SIFT predicts this variant to be "deleterious". In summary, the variant is unlikely to be causing disease as it is present in the general population at an elevated frequency, evidence suggests it may only cause disease when inherited in the homozygous form, furthermore the variant has not been identified in consistent phenotypes and 2/3 in silico tools predict the variant to be benign, therefore we classify TPM1 Gly3Arg as 'likely benign'. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at