rs878854753
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_005159.5(ACTC1):c.129G>A(p.Gln43=) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_005159.5 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTC1 | NM_005159.5 | c.129G>A | p.Gln43= | splice_region_variant, synonymous_variant | 2/7 | ENST00000290378.6 | |
GJD2-DT | NR_120329.1 | n.300-15816C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTC1 | ENST00000290378.6 | c.129G>A | p.Gln43= | splice_region_variant, synonymous_variant | 2/7 | 1 | NM_005159.5 | P1 | |
GJD2-DT | ENST00000671663.1 | n.95-15816C>T | intron_variant, non_coding_transcript_variant | ||||||
ACTC1 | ENST00000560563.2 | n.235G>A | splice_region_variant, non_coding_transcript_exon_variant | 2/6 | 2 | ||||
GJD2-DT | ENST00000503496.6 | n.300-15816C>T | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152216Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74374
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 11;C2748552:Atrial septal defect 5;C3150681:Dilated cardiomyopathy 1R Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 01, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 10, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change affects codon 43 of the ACTC1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ACTC1 protein. This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hypertrophic cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 240098). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 28, 2023 | This synonymous variant alters the conserved c.G at the last nucleotide of exon 2 of the ACTC1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with ACTC1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 12, 2023 | The c.129G>A variant (also known as p.Q43Q), located in coding exon 1 of the ACTC1 gene. This variant results from a G to A substitution at nucleotide position 129. This nucleotide substitution does not change the glutamine at codon 43. However, this change occurs in the last base pair of coding exon 1, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at