NM_001614.5:c.1128A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001614.5(ACTG1):c.1128A>G(p.Ter376Ter) variant causes a stop retained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,613,942 control chromosomes in the GnomAD database, including 640 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.040 ( 224 hom., cov: 32)

Exomes 𝑓: 0.017 ( 416 hom. )

Consequence

ACTG1
NM_001614.5 stop_retained

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.03

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

Baraitser-winter syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
autosomal dominant nonsyndromic hearing loss 20
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Baraitser-Winter cerebrofrontofacial syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACTG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 17-81510690-T-C is Benign according to our data. Variant chr17-81510690-T-C is described in ClinVar as [Benign]. Clinvar id is 128269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.03 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.098 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTG1	NM_001614.5 link	c.1128A>G	p.Ter376Ter	stop_retained_variant	Exon 6 of 6	ENST00000573283.7	NP_001605.1	P63261
ACTG1	NM_001199954.3 link	c.1128A>G	p.Ter376Ter	stop_retained_variant	Exon 6 of 6		NP_001186883.1	P63261
ACTG1	NR_037688.3 link	n.1200A>G		non_coding_transcript_exon_variant	Exon 6 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTG1	ENST00000573283.7 link	c.1128A>G	p.Ter376Ter	stop_retained_variant	Exon 6 of 6	5	NM_001614.5	ENSP00000458435.1		P63261

Frequencies

GnomAD3 genomes

AF:

0.0403

AC:

6126

AN:

152160

Hom.:

226

Cov.:

show subpopulations

Gnomad AFR

AF:

0.101

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0300

Gnomad ASJ

AF:

0.0513

Gnomad EAS

AF:

0.0331

Gnomad SAS

AF:

0.0172

Gnomad FIN

AF:

0.00556

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0135

Gnomad OTH

AF:

0.0411

GnomAD2 exomes

AF:

0.0225

AC:

5654

AN:

251408

AF XY:

0.0208

show subpopulations

Gnomad AFR exome

AF:

0.100

Gnomad AMR exome

AF:

0.0194

Gnomad ASJ exome

AF:

0.0486

Gnomad EAS exome

AF:

0.0303

Gnomad FIN exome

AF:

0.00637

Gnomad NFE exome

AF:

0.0134

Gnomad OTH exome

AF:

0.0212

GnomAD4 exome

AF:

0.0165

AC:

24139

AN:

1461664

Hom.:

416

Cov.:

AF XY:

0.0163

AC XY:

11846

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.0991

AC:

3318

AN:

33476

American (AMR)

AF:

0.0199

AC:

890

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0499

AC:

1303

AN:

26134

East Asian (EAS)

AF:

0.0228

AC:

906

AN:

39700

South Asian (SAS)

AF:

0.0170

AC:

1470

AN:

86246

European-Finnish (FIN)

AF:

0.00573

AC:

306

AN:

53362

Middle Eastern (MID)

AF:

0.0255

AC:

145

AN:

5694

European-Non Finnish (NFE)

AF:

0.0129

AC:

14371

AN:

1111948

Other (OTH)

AF:

0.0237

AC:

1430

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

1500

3000

4499

5999

7499

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0403

AC:

6135

AN:

152278

Hom.:

224

Cov.:

AF XY:

0.0399

AC XY:

2969

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.100

AC:

4176

AN:

41554

American (AMR)

AF:

0.0300

AC:

459

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0513

AC:

178

AN:

3472

East Asian (EAS)

AF:

0.0330

AC:

171

AN:

5180

South Asian (SAS)

AF:

0.0170

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00556

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0135

AC:

916

AN:

68026

Other (OTH)

AF:

0.0411

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

303

605

908

1210

1513

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0256

Hom.:

Bravo

AF:

0.0439

Asia WGS

AF:

0.0400

AC:

137

AN:

3478

EpiCase

AF:

0.0162

EpiControl

AF:

0.0158

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 04, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 11, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

X376X in exon 6 of ACTG1: This variant is not expected to have clinical signific ance because it does not alter the termination codon, it is not located within t he splice consensus sequence, it has been identified in 1.3% (113/8600) of Europ ean American chromosomes and 9% (395/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washingt on.edu/EVS/; dbSNP rs11549223) -

Nov 13, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

May 23, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Autosomal dominant nonsyndromic hearing loss 20

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Baraitser-winter syndrome 2

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 20;C3281235:Baraitser-winter syndrome 2

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

7.5

(source)

DANN

Benign

0.72

PhyloP100

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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NM_001614.5:c.1128A>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over