17-81510804-C-T

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.1014G>A(p.Ser338Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,613,884 control chromosomes in the GnomAD database, including 638 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.040 ( 222 hom., cov: 32)

Exomes 𝑓: 0.017 ( 416 hom. )

Consequence

ACTG1
NM_001614.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -11.0

Publications

12 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=-0.77).

BP6

Variant 17-81510804-C-T is Benign according to our data. Variant chr17-81510804-C-T is described in ClinVar as Benign. ClinVar VariationId is 128267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-11 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.1014G>A	p.Ser338Ser	synonymous_variant	Exon 6 of 6	ENST00000573283.7	NP_001605.1	P63261
ACTG1	NM_001199954.3 link	c.1014G>A	p.Ser338Ser	synonymous_variant	Exon 6 of 6		NP_001186883.1	P63261
ACTG1	NR_037688.3 link	n.1086G>A		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.1014G>A	p.Ser338Ser	synonymous_variant	Exon 6 of 6	5	NM_001614.5	ENSP00000458435.1		P63261

Frequencies

GnomAD3 genomes

AF:

0.0403

AC:

6122

AN:

152086

Hom.:

224

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:

0.0334

Gnomad SAS

AF:

0.0168

Gnomad FIN

AF:

0.00556

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0135

Gnomad OTH

AF:

0.0412

GnomAD2 exomes

AF:

0.0225

AC:

5646

AN:

251318

AF XY:

0.0208

show subpopulations

Gnomad AFR exome

AF:

0.0997

Gnomad AMR exome

AF:

0.0195

Gnomad ASJ exome

AF:

0.0485

Gnomad EAS exome

AF:

0.0302

Gnomad FIN exome

AF:

0.00638

Gnomad NFE exome

AF:

0.0134

Gnomad OTH exome

AF:

0.0212

GnomAD4 exome

AF:

0.0165

AC:

24149

AN:

1461680

Hom.:

416

Cov.:

AF XY:

0.0163

AC XY:

11849

AN XY:

727144

show subpopulations

African (AFR)

AF:

0.0991

AC:

3317

AN:

33476

American (AMR)

AF:

0.0200

AC:

893

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0499

AC:

1303

AN:

26136

East Asian (EAS)

AF:

0.0223

AC:

885

AN:

39700

South Asian (SAS)

AF:

0.0171

AC:

1473

AN:

86252

European-Finnish (FIN)

AF:

0.00574

AC:

306

AN:

53284

Middle Eastern (MID)

AF:

0.0277

AC:

160

AN:

5766

European-Non Finnish (NFE)

AF:

0.0129

AC:

14383

AN:

1111962

Other (OTH)

AF:

0.0237

AC:

1429

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

1622

3245

4867

6490

8112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

636

1272

1908

2544

3180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0403

AC:

6131

AN:

152204

Hom.:

222

Cov.:

AF XY:

0.0399

AC XY:

2966

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.101

AC:

4171

AN:

41502

American (AMR)

AF:

0.0300

AC:

459

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0513

AC:

178

AN:

3472

East Asian (EAS)

AF:

0.0332

AC:

172

AN:

5174

South Asian (SAS)

AF:

0.0166

AC:

AN:

4824

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:

918

AN:

68020

Other (OTH)

AF:

0.0413

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

295

590

885

1180

1475

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0281

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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. -

Feb 20, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ser338Ser in Exon 06 of ACTG1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 8.3% (310/3738) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs1139807). -

not provided

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

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

- -

Baraitser-winter syndrome 2

Benign:1

Dec 05, 2021

Genome-Nilou Lab

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

-0.77

CADD

Benign

0.16

(source)

DANN

Benign

0.88

PhyloP100

-11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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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