rs1135989

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.930C>T(p.Ala310Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 1,613,808 control chromosomes in the GnomAD database, including 104,483 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A310A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.30 ( 7714 hom., cov: 33)

Exomes 𝑓: 0.35 ( 96769 hom. )

Consequence

ACTG1
NM_001614.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -2.40

Publications

34 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 17-81510981-G-A is Benign according to our data. Variant chr17-81510981-G-A is described in ClinVar as Benign. ClinVar VariationId is 44151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.39 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTG1	NM_001614.5 link	c.930C>T	p.Ala310Ala	synonymous_variant	Exon 5 of 6	ENST00000573283.7	NP_001605.1	P63261
ACTG1	NM_001199954.3 link	c.930C>T	p.Ala310Ala	synonymous_variant	Exon 5 of 6		NP_001186883.1	P63261
ACTG1	NR_037688.3 link	n.1002C>T		non_coding_transcript_exon_variant	Exon 5 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTG1	ENST00000573283.7 link	c.930C>T	p.Ala310Ala	synonymous_variant	Exon 5 of 6	5	NM_001614.5	ENSP00000458435.1		P63261

Frequencies

GnomAD3 genomes

AF:

0.300

AC:

45656

AN:

151958

Hom.:

7716

Cov.:

show subpopulations

Gnomad AFR

AF:

0.188

Gnomad AMI

AF:

0.214

Gnomad AMR

AF:

0.260

Gnomad ASJ

AF:

0.344

Gnomad EAS

AF:

0.00520

Gnomad SAS

AF:

0.165

Gnomad FIN

AF:

0.415

Gnomad MID

AF:

0.229

Gnomad NFE

AF:

0.391

Gnomad OTH

AF:

0.310

GnomAD2 exomes

AF:

0.287

AC:

72134

AN:

251338

AF XY:

0.290

show subpopulations

Gnomad AFR exome

AF:

0.188

Gnomad AMR exome

AF:

0.183

Gnomad ASJ exome

AF:

0.335

Gnomad EAS exome

AF:

0.00163

Gnomad FIN exome

AF:

0.416

Gnomad NFE exome

AF:

0.380

Gnomad OTH exome

AF:

0.332

GnomAD4 exome

AF:

0.350

AC:

512264

AN:

1461732

Hom.:

96769

Cov.:

AF XY:

0.346

AC XY:

251336

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.180

AC:

6035

AN:

33472

American (AMR)

AF:

0.191

AC:

8563

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.342

AC:

8946

AN:

26136

East Asian (EAS)

AF:

0.00116

AC:

AN:

39700

South Asian (SAS)

AF:

0.177

AC:

15231

AN:

86256

European-Finnish (FIN)

AF:

0.412

AC:

21953

AN:

53332

Middle Eastern (MID)

AF:

0.225

AC:

1298

AN:

5760

European-Non Finnish (NFE)

AF:

0.387

AC:

430585

AN:

1111962

Other (OTH)

AF:

0.325

AC:

19607

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

22615

45230

67845

90460

113075

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13058

26116

39174

52232

65290

<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:

0.300

AC:

45636

AN:

152076

Hom.:

7714

Cov.:

AF XY:

0.297

AC XY:

22063

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.188

AC:

7800

AN:

41498

American (AMR)

AF:

0.259

AC:

3961

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.344

AC:

1193

AN:

3470

East Asian (EAS)

AF:

0.00521

AC:

AN:

5182

South Asian (SAS)

AF:

0.163

AC:

786

AN:

4816

European-Finnish (FIN)

AF:

0.415

AC:

4383

AN:

10564

Middle Eastern (MID)

AF:

0.219

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.391

AC:

26585

AN:

67968

Other (OTH)

AF:

0.305

AC:

642

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1578

3156

4734

6312

7890

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

446

892

1338

1784

2230

<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:

0.328

Hom.:

3709

Bravo

AF:

0.281

Asia WGS

AF:

0.0760

AC:

265

AN:

3478

EpiCase

AF:

0.381

EpiControl

AF:

0.377

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ala310Ala in Exon 05 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 37.7% (2650/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1135989). -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 28, 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. -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 20

Benign:1

Jul 14, 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 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Baraitser-winter syndrome 2

Benign:1

Jul 14, 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

-0.61

CADD

Benign

2.4

(source)

DANN

Benign

0.93

PhyloP100

-2.4

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)

0.0

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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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