rs1135989

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001614.5(ACTG1):c.930C>T(p.Ala310=) 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 (★★).

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:8

Conservation

PhyloP100: -2.40

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 44151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-81510981-G-A is described in Lovd as [Likely_benign]. Variant chr17-81510981-G-A is described in Lovd as [Benign].

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/exons	MANE
ACTG1	NM_001614.5 linkuse as main transcript	c.930C>T	p.Ala310=	synonymous_variant	5/6	ENST00000573283.7
ACTG1	NM_001199954.3 linkuse as main transcript	c.930C>T	p.Ala310=	synonymous_variant	5/6
ACTG1	NR_037688.3 linkuse as main transcript	n.1002C>T		non_coding_transcript_exon_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTG1	ENST00000573283.7 linkuse as main transcript	c.930C>T	p.Ala310=	synonymous_variant	5/6	5	NM_001614.5	P4

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

GnomAD3 exomes

AF:

0.287

AC:

72134

AN:

251338

Hom.:

12651

AF XY:

0.290

AC XY:

39353

AN XY:

135868

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 SAS exome

AF:

0.167

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

Gnomad4 AFR exome

AF:

0.180

Gnomad4 AMR exome

AF:

0.191

Gnomad4 ASJ exome

AF:

0.342

Gnomad4 EAS exome

AF:

0.00116

Gnomad4 SAS exome

AF:

0.177

Gnomad4 FIN exome

AF:

0.412

Gnomad4 NFE exome

AF:

0.387

Gnomad4 OTH exome

AF:

0.325

GnomAD4 genome

AF:

0.300

AC:

45636

AN:

152076

Hom.:

7714

Cov.:

AF XY:

0.297

AC XY:

22063

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.188

Gnomad4 AMR

AF:

0.259

Gnomad4 ASJ

AF:

0.344

Gnomad4 EAS

AF:

0.00521

Gnomad4 SAS

AF:

0.163

Gnomad4 FIN

AF:

0.415

Gnomad4 NFE

AF:

0.391

Gnomad4 OTH

AF:

0.305

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	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). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Autosomal dominant nonsyndromic hearing loss 20

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Baraitser-winter syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

Cadd

Benign

2.4

Dann

Benign

0.93

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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