rs182162229
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_001614.5(ACTG1):c.654C>T(p.Tyr218=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00023 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00023 ( 0 hom. )
Consequence
ACTG1
NM_001614.5 synonymous
NM_001614.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.223
Genes affected
ACTG1 (HGNC:144): (actin gamma 1) Actins are highly conserved proteins that are involved in various types of cell motility and in maintenance of the cytoskeleton. Three main groups of actin isoforms have been identified in vertebrate animals: alpha, beta, and gamma. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. The beta and gamma actins co-exist in most cell types as components of the cytoskeleton and as mediators of internal cell motility. Actin gamma 1, encoded by this gene, is a cytoplasmic actin found in all cell types. Mutations in this gene are associated with DFNA20/26, a subtype of autosomal dominant non-syndromic sensorineural progressive hearing loss and also with Baraitser-Winter syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2017]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.55).
BP6
?
Variant 17-81511336-G-A is Benign according to our data. Variant chr17-81511336-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434076.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1}.
BP7
?
Synonymous conserved (PhyloP=0.223 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00023 (35/152356) while in subpopulation NFE AF= 0.000397 (27/68032). AF 95% confidence interval is 0.00028. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 35 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTG1 | NM_001614.5 | c.654C>T | p.Tyr218= | synonymous_variant | 4/6 | ENST00000573283.7 | |
ACTG1 | NM_001199954.3 | c.654C>T | p.Tyr218= | synonymous_variant | 4/6 | ||
ACTG1 | NR_037688.3 | n.726C>T | non_coding_transcript_exon_variant | 4/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTG1 | ENST00000573283.7 | c.654C>T | p.Tyr218= | synonymous_variant | 4/6 | 5 | NM_001614.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000230 AC: 35AN: 152238Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000207 AC: 52AN: 250816Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135724
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GnomAD4 exome AF: 0.000234 AC: 342AN: 1461524Hom.: 0 Cov.: 37 AF XY: 0.000232 AC XY: 169AN XY: 727084
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GnomAD4 genome ? AF: 0.000230 AC: 35AN: 152356Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18AN XY: 74508
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | ACTG1: BP4, BP7 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 24, 2021 | - - |
Baraitser-winter syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 25, 2015 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 30, 2012 | Tyr218Tyr in Exon 04 of ACTG1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 1/7018 European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS). - |
ACTG1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 09, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Autosomal dominant nonsyndromic hearing loss 20;C3281235:Baraitser-winter syndrome 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at