rs876657740

Variant names:

Your query was ambiguous. Multiple possible variants found:

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

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]

ACTG1 links:

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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 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, 0.969

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTG1	NM_001614.5 link	c.377C>T	p.Thr126Ile	missense_variant	Exon 4 of 6	ENST00000573283.7	NP_001605.1	P63261
ACTG1	NM_001199954.3 link	c.377C>T	p.Thr126Ile	missense_variant	Exon 4 of 6		NP_001186883.1	P63261
ACTG1	NR_037688.3 link	n.449C>T		non_coding_transcript_exon_variant	Exon 4 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTG1	ENST00000573283.7 link	c.377C>T	p.Thr126Ile	missense_variant	Exon 4 of 6	5	NM_001614.5	ENSP00000458435.1		P63261

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249718

Hom.:

AF XY:

0.00

AC XY:

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:

AN:

1461152

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

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.:

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

Feb 18, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

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

LIST_S2

Benign

0.72

.;.;T;.;.;.;T;.;T;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

H;H;H;H;H;H;.;.;.;.

PrimateAI

Pathogenic

0.80

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over