rs1139406

chr17-81510792-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001614.5(ACTG1):c.1026T>C(p.Gly342=) 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 1,612,654 control chromosomes in the GnomAD database, including 637 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (222 hom., cov: 32)
  • Exomes 𝑓: 0.017 (415 hom.)
• Consequence: ACTG1 NM_001614.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.01

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-81510792-A-G is Benign according to our data. Variant chr17-81510792-A-G is described in ClinVar as [Benign]. Clinvar id is 128268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-81510792-A-G is described in Lovd as [Likely_benign]. Variant chr17-81510792-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0988 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTG1	NM_001614.5	c.1026T>C	p.Gly342=	synonymous_variant	6/6	ENST00000573283.7
ACTG1	NM_001199954.3	c.1026T>C	p.Gly342=	synonymous_variant	6/6
ACTG1	NR_037688.3	n.1098T>C		non_coding_transcript_exon_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTG1	ENST00000573283.7	c.1026T>C	p.Gly342=	synonymous_variant	6/6	5	NM_001614.5	P4

Frequencies

GnomAD3 genomes AF: 0.0405 AC: 6115 AN: 150880 Hom.: 224 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00333

Gnomad AMR AF: 0.0302

Gnomad ASJ AF: 0.0516

Gnomad EAS AF: 0.0339

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.00548

Gnomad MID AF: 0.0128

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.0417

GnomAD3 exomes AF: 0.0225 AC: 5645 AN: 251294 Hom.: 138 AF XY: 0.0208 AC XY: 2824 AN XY: 135874

Gnomad AFR exome AF: 0.0999

Gnomad AMR exome AF: 0.0194

Gnomad ASJ exome AF: 0.0485

Gnomad EAS exome AF: 0.0302

Gnomad SAS exome AF: 0.0170

Gnomad FIN exome AF: 0.00638

Gnomad NFE exome AF: 0.0134

Gnomad OTH exome AF: 0.0210

GnomAD4 exome AF: 0.0165 AC: 24137 AN: 1461654 Hom.: 415 Cov.: 30 AF XY: 0.0163 AC XY: 11845 AN XY: 727138

Gnomad4 AFR exome AF: 0.0991

Gnomad4 AMR exome AF: 0.0199

Gnomad4 ASJ exome AF: 0.0499

Gnomad4 EAS exome AF: 0.0223

Gnomad4 SAS exome AF: 0.0170

Gnomad4 FIN exome AF: 0.00573

Gnomad4 NFE exome AF: 0.0129

Gnomad4 OTH exome AF: 0.0237

GnomAD4 genome AF: 0.0406 AC: 6124 AN: 151000 Hom.: 222 Cov.: 32 AF XY: 0.0402 AC XY: 2965 AN XY: 73820

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0302

Gnomad4 ASJ AF: 0.0516

Gnomad4 EAS AF: 0.0338

Gnomad4 SAS AF: 0.0170

Gnomad4 FIN AF: 0.00548

Gnomad4 NFE AF: 0.0136

Gnomad4 OTH AF: 0.0417

Alfa AF: 0.0272 Hom.: 54

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Gly342Gly 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% (311/3738) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs1139406). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 20, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -

Autosomal dominant nonsyndromic hearing loss 20 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 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

- -

Baraitser-winter syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.62
Dann	Benign	0.51
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

Other links and lift over

dbSNP: rs1139406; hg19: chr17-79477818;