rs876657740
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 7P and 4B. PM2PP2PP3_StrongBS2
The NM_001614.5(ACTG1):c.377C>T(p.Thr126Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001614.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACTG1 | NM_001614.5 | c.377C>T | p.Thr126Ile | missense_variant | 4/6 | ENST00000573283.7 | NP_001605.1 | |
ACTG1 | NM_001199954.3 | c.377C>T | p.Thr126Ile | missense_variant | 4/6 | NP_001186883.1 | ||
ACTG1 | NR_037688.3 | n.449C>T | non_coding_transcript_exon_variant | 4/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ACTG1 | ENST00000573283.7 | c.377C>T | p.Thr126Ile | missense_variant | 4/6 | 5 | NM_001614.5 | ENSP00000458435 | P4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 249718Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135360
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461152Hom.: 0 Cov.: 37 AF XY: 0.00000413 AC XY: 3AN XY: 726870
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 18, 2015 | The p.Thr126Ile variant in ACTG1 has not been previously reported in individuals with hearing loss or in large population studies. Computational prediction tool s and conservation analysis suggest that the variant may impact the protein, tho ugh this information is not predictive enough to determine pathogenicity. In sum mary, the clinical significance of the p.Thr126Ile variant is uncertain. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 20, 2021 | The c.377C>T (p.T126I) alteration is located in exon 4 (coding exon 3) of the ACTG1 gene. This alteration results from a C to T substitution at nucleotide position 377, causing the threonine (T) at amino acid position 126 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Autosomal dominant nonsyndromic hearing loss 20;C3281235:Baraitser-winter syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 22, 2023 | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 126 of the ACTG1 protein (p.Thr126Ile). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with ACTG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 228432). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACTG1 protein function with a negative predictive value of 80%. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at