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

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ACTG1
NM_001614.5 missense

Scores

14
2
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

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 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTG1. . Gene score misZ 3.16 (greater than the threshold 3.09). Trascript score misZ 4.8823 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.969
BS2
High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ACTG1NM_001614.5 linkuse as main transcriptc.377C>T p.Thr126Ile missense_variant 4/6 ENST00000573283.7 NP_001605.1
ACTG1NM_001199954.3 linkuse as main transcriptc.377C>T p.Thr126Ile missense_variant 4/6 NP_001186883.1
ACTG1NR_037688.3 linkuse as main transcriptn.449C>T non_coding_transcript_exon_variant 4/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ACTG1ENST00000573283.7 linkuse as main transcriptc.377C>T p.Thr126Ile missense_variant 4/65 NM_001614.5 ENSP00000458435 P4

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000400
AC:
1
AN:
249718
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135360
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461152
Hom.:
0
Cov.:
37
AF XY:
0.00000413
AC XY:
3
AN XY:
726870
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000227

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 18, 2015The 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 submitterclinical testingAmbry GeneticsMay 20, 2021The 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 22, 2023This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.52
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.93
D;D;D;D;D;D;D;D;D;D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.72
.;.;T;.;.;.;T;.;T;D
M_CAP
Pathogenic
0.94
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.2
H;H;H;H;H;H;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.80
D
PROVEAN
Pathogenic
-4.5
.;D;.;.;.;.;.;.;.;.
REVEL
Pathogenic
0.96
Sift4G
Uncertain
0.0030
D;D;D;D;D;.;.;.;D;D
Polyphen
0.99
D;D;D;D;D;D;.;.;.;.
Vest4
0.86
MutPred
0.81
Gain of catalytic residue at A131 (P = 0.3019);Gain of catalytic residue at A131 (P = 0.3019);Gain of catalytic residue at A131 (P = 0.3019);Gain of catalytic residue at A131 (P = 0.3019);Gain of catalytic residue at A131 (P = 0.3019);Gain of catalytic residue at A131 (P = 0.3019);.;Gain of catalytic residue at A131 (P = 0.3019);Gain of catalytic residue at A131 (P = 0.3019);Gain of catalytic residue at A131 (P = 0.3019);
MVP
0.98
ClinPred
0.97
D
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.92
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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