17-81511613-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_001614.5(ACTG1):​c.377C>G​(p.Thr126Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 33)

Consequence

ACTG1
NM_001614.5 missense

Scores

9
5
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.44
Variant links:
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 Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the ACTG1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 49 curated pathogenic missense variants (we use a threshold of 10). The gene has 48 curated benign missense variants. Gene score misZ: 3.16 (above the threshold of 3.09). Trascript score misZ: 4.8823 (above the threshold of 3.09). GenCC associations: The gene is linked to Baraitser-winter syndrome 2, autosomal dominant nonsyndromic hearing loss, nonsyndromic genetic hearing loss, Baraitser-Winter cerebrofrontofacial syndrome, autosomal dominant nonsyndromic hearing loss 20.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.901

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACTG1NM_001614.5 linkc.377C>G p.Thr126Ser missense_variant Exon 4 of 6 ENST00000573283.7 NP_001605.1 P63261
ACTG1NM_001199954.3 linkc.377C>G p.Thr126Ser missense_variant Exon 4 of 6 NP_001186883.1 P63261
ACTG1NR_037688.3 linkn.449C>G non_coding_transcript_exon_variant Exon 4 of 7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACTG1ENST00000573283.7 linkc.377C>G p.Thr126Ser missense_variant Exon 4 of 6 5 NM_001614.5 ENSP00000458435.1 P63261

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152226
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
37
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152226
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.66
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.21
CADD
Pathogenic
32
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.90
D;D;D;D;D;D;D;D;D;D
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.79
.;.;T;.;.;.;T;.;T;T
M_CAP
Pathogenic
0.80
D
MetaRNN
Pathogenic
0.90
D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Benign
1.6
L;L;L;L;L;L;.;.;.;.
PrimateAI
Uncertain
0.73
T
PROVEAN
Uncertain
-2.8
.;D;.;.;.;.;.;.;.;.
REVEL
Pathogenic
0.85
Sift4G
Benign
0.11
T;T;T;T;T;.;.;.;T;T
Polyphen
0.54
P;P;P;P;P;P;.;.;.;.
Vest4
0.69
MutPred
0.68
Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);.;Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);
MVP
0.96
ClinPred
0.98
D
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.89
gMVP
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs876657740; hg19: chr17-79478639; API