chr17-81510993-G-A

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.918C>T(p.Tyr306Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.801 in 1,613,832 control chromosomes in the GnomAD database, including 519,901 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.76 ( 44684 hom., cov: 32)

Exomes 𝑓: 0.81 ( 475217 hom. )

Consequence

ACTG1
NM_001614.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.79

Publications

39 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=-0.54).

BP6

Variant 17-81510993-G-A is Benign according to our data. Variant chr17-81510993-G-A is described in ClinVar as Benign. ClinVar VariationId is 44150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.79 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.837 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTG1	NM_001614.5 link	c.918C>T	p.Tyr306Tyr	synonymous_variant	Exon 5 of 6	ENST00000573283.7	NP_001605.1	P63261
ACTG1	NM_001199954.3 link	c.918C>T	p.Tyr306Tyr	synonymous_variant	Exon 5 of 6		NP_001186883.1	P63261
ACTG1	NR_037688.3 link	n.990C>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.918C>T	p.Tyr306Tyr	synonymous_variant	Exon 5 of 6	5	NM_001614.5	ENSP00000458435.1		P63261

Frequencies

GnomAD3 genomes

AF:

0.762

AC:

115797

AN:

151986

Hom.:

44671

Cov.:

show subpopulations

Gnomad AFR

AF:

0.631

Gnomad AMI

AF:

0.871

Gnomad AMR

AF:

0.739

Gnomad ASJ

AF:

0.814

Gnomad EAS

AF:

0.858

Gnomad SAS

AF:

0.792

Gnomad FIN

AF:

0.835

Gnomad MID

AF:

0.737

Gnomad NFE

AF:

0.821

Gnomad OTH

AF:

0.777

GnomAD2 exomes

AF:

0.788

AC:

198064

AN:

251344

AF XY:

0.793

show subpopulations

Gnomad AFR exome

AF:

0.629

Gnomad AMR exome

AF:

0.690

Gnomad ASJ exome

AF:

0.804

Gnomad EAS exome

AF:

0.877

Gnomad FIN exome

AF:

0.837

Gnomad NFE exome

AF:

0.816

Gnomad OTH exome

AF:

0.800

GnomAD4 exome

AF:

0.805

AC:

1177071

AN:

1461728

Hom.:

475217

Cov.:

AF XY:

0.806

AC XY:

585879

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.626

AC:

20955

AN:

33474

American (AMR)

AF:

0.698

AC:

31198

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.810

AC:

21174

AN:

26134

East Asian (EAS)

AF:

0.822

AC:

32619

AN:

39700

South Asian (SAS)

AF:

0.788

AC:

67942

AN:

86256

European-Finnish (FIN)

AF:

0.835

AC:

44524

AN:

53314

Middle Eastern (MID)

AF:

0.750

AC:

4320

AN:

5760

European-Non Finnish (NFE)

AF:

0.815

AC:

906344

AN:

1111978

Other (OTH)

AF:

0.795

AC:

47995

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

16575

33150

49726

66301

82876

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20860

41720

62580

83440

104300

<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:

0.762

AC:

115848

AN:

152104

Hom.:

44684

Cov.:

AF XY:

0.763

AC XY:

56731

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.631

AC:

26169

AN:

41466

American (AMR)

AF:

0.739

AC:

11276

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.814

AC:

2825

AN:

3470

East Asian (EAS)

AF:

0.858

AC:

4432

AN:

5166

South Asian (SAS)

AF:

0.793

AC:

3816

AN:

4814

European-Finnish (FIN)

AF:

0.835

AC:

8838

AN:

10588

Middle Eastern (MID)

AF:

0.724

AC:

213

AN:

294

European-Non Finnish (NFE)

AF:

0.821

AC:

55841

AN:

68014

Other (OTH)

AF:

0.778

AC:

1644

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1341

2682

4022

5363

6704

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

856

1712

2568

3424

4280

<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:

0.790

Hom.:

22027

Bravo

AF:

0.748

Asia WGS

AF:

0.776

AC:

2697

AN:

3478

EpiCase

AF:

0.813

EpiControl

AF:

0.811

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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. -

Oct 15, 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. -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Tyr306Tyr 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 35.7% (1333/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1139405). -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

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

- -

not provided

Benign:2

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

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

- -

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

-0.54

CADD

Benign

3.1

(source)

DANN

Benign

0.94

PhyloP100

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=92/8

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