rs765321518
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_005681.4(TAF1A):c.1021G>A(p.Gly341Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,612,710 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 Uncertain significance (★★).
Frequency
Consequence
NM_005681.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TAF1A | ENST00000352967.9 | c.1021G>A | p.Gly341Arg | missense_variant | Exon 9 of 11 | 1 | NM_005681.4 | ENSP00000327072.6 | ||
TAF1A | ENST00000350027.8 | c.1021G>A | p.Gly341Arg | missense_variant | Exon 9 of 12 | 2 | ENSP00000339976.4 | |||
TAF1A | ENST00000366890.5 | c.679G>A | p.Gly227Arg | missense_variant | Exon 8 of 11 | 2 | ENSP00000355856.1 | |||
TAF1A | ENST00000391883.2 | c.*48G>A | downstream_gene_variant | 5 | ENSP00000375755.2 |
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 152036Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000280 AC: 7AN: 250252Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135322
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1460674Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14AN XY: 726700
GnomAD4 genome AF: 0.0000395 AC: 6AN: 152036Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74282
ClinVar
Submissions by phenotype
not provided Uncertain:1
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Cardiomyopathy, familial restrictive, 6 Uncertain:1
The paternally inherited c.1021G>A, p.Gly341Arg variant in the TAF1A gene in this affected child is a missense variant, which results in a substitution of Glycine residue to Arginine at position 341/451 of the protein, predicted to be damaging by multiple in silico prediction tools (SIFT and PROVEAN). This variant is rare from the gnomAD database with allele frequency 0.00002797 (7/250252 heterozygotes, 0 homozygote) indicating that it is not a common benign occurrence in the populations represented in the database. This variant has been previously reported in two cardiomyopathy sisters (2-3 years old) in compound heterozygous state with another missense variant in the TAF1A gene (PMID: 28472305). TAF1A encodes a TATA box-binding protein-associated factor which is required for RNA polymerase I to synthesize ribosomal RNA. In one study, the TAF1A gene specific subcellular phenotype was identified in approximately 50% of the cardiomyocytes of the affected sisters and was absent in pediatric normal and DCM controls. In a functional study of this gene, TAF1A-/- zebrafish recapitulate a heart failure phenotype (PMID: 28472305). However, since only one pediatric cardiomyopathy family has been reported with compound heterozygous TAF1A variants, the gene-disease association for TAF1A with pediatric cardiomyopathy remains uncertain. Given these evidences, TAF1A is a gene of unknown significance and therefore the c.1021G>A, p.Gly341Arg variant is classified as variant of unknown significance. -
Primary dilated cardiomyopathy Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at