15-34794740-A-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong
The NM_005159.5(ACTC1):c.69T>A(p.Phe23Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_005159.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ACTC1 | ENST00000290378.6 | c.69T>A | p.Phe23Leu | missense_variant | Exon 2 of 7 | 1 | NM_005159.5 | ENSP00000290378.4 | ||
ACTC1 | ENST00000560563.2 | n.175T>A | non_coding_transcript_exon_variant | Exon 2 of 6 | 2 | |||||
GJD2-DT | ENST00000503496.6 | n.300-15756A>T | intron_variant | Intron 2 of 2 | 2 | |||||
GJD2-DT | ENST00000671663.1 | n.95-15756A>T | intron_variant | Intron 1 of 1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:1
The c.69 T>A nucleotide substitution, resulting in the F23L amino acid change in this individual, has not been reported previously as a pathogenic or benign variant to our knowledge. However, a different nucleotide substitution (c.67 T>C) that also results in the F23L missense substitution was previously reported in association with cardiomyopathy (Coppini et al., 2014). The F23L (c.69 T>A) variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species and in silico analysis suggests that this variant is probably damaging to the protein structure/function. Nevertheless, the F23L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at