chr1-229432557-G-C
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7
The NM_001100.4(ACTA1):āc.453C>Gā(p.Thr151=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000932 in 1,609,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T151T) has been classified as Likely benign.
Frequency
Consequence
NM_001100.4 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTA1 | NM_001100.4 | c.453C>G | p.Thr151= | splice_region_variant, synonymous_variant | 3/7 | ENST00000366684.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTA1 | ENST00000366684.7 | c.453C>G | p.Thr151= | splice_region_variant, synonymous_variant | 3/7 | 1 | NM_001100.4 | P1 | |
ACTA1 | ENST00000366683.4 | c.453C>G | p.Thr151= | splice_region_variant, synonymous_variant | 3/7 | 5 | |||
ACTA1 | ENST00000684723.1 | c.318C>G | p.Thr106= | splice_region_variant, synonymous_variant | 2/6 |
Frequencies
GnomAD3 genomes AF: 0.00000660 AC: 1AN: 151608Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000406 AC: 10AN: 246562Hom.: 0 AF XY: 0.0000374 AC XY: 5AN XY: 133768
GnomAD4 exome AF: 0.00000960 AC: 14AN: 1457812Hom.: 0 Cov.: 37 AF XY: 0.00000965 AC XY: 7AN XY: 725090
GnomAD4 genome AF: 0.00000660 AC: 1AN: 151608Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74040
ClinVar
Submissions by phenotype
Actin accumulation myopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 02, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change affects codon 151 of the ACTA1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ACTA1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs76030344, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with ACTA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 873885). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. - |
Familial restrictive cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 02, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Congenital myopathy with fiber type disproportion Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 02, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at