rs1139405

chr17-81510993-G-Achr17-81510993-G-Cchr17-81510993-G-T

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.918C>T(p.Tyr306=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.79

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=-0.54).
• BP6: Variant 17-81510993-G-A is Benign according to our data. Variant chr17-81510993-G-A is described in ClinVar as [Benign]. Clinvar id is 44150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-81510993-G-A is described in Lovd as [Likely_benign]. Variant chr17-81510993-G-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
ACTG1	NM_001614.5	c.918C>T	p.Tyr306=	synonymous_variant	5/6	ENST00000573283.7
ACTG1	NM_001199954.3	c.918C>T	p.Tyr306=	synonymous_variant	5/6
ACTG1	NR_037688.3	n.990C>T		non_coding_transcript_exon_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTG1	ENST00000573283.7	c.918C>T	p.Tyr306=	synonymous_variant	5/6	5	NM_001614.5	P4

Frequencies

GnomAD3 genomes AF: 0.762 AC: 115797 AN: 151986 Hom.: 44671 Cov.: 32

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

GnomAD3 exomes AF: 0.788 AC: 198064 AN: 251344 Hom.: 78611 AF XY: 0.793 AC XY: 107764 AN XY: 135874

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 SAS exome AF: 0.784

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.: 90 AF XY: 0.806 AC XY: 585879 AN XY: 727180

Gnomad4 AFR exome AF: 0.626

Gnomad4 AMR exome AF: 0.698

Gnomad4 ASJ exome AF: 0.810

Gnomad4 EAS exome AF: 0.822

Gnomad4 SAS exome AF: 0.788

Gnomad4 FIN exome AF: 0.835

Gnomad4 NFE exome AF: 0.815

Gnomad4 OTH exome AF: 0.795

GnomAD4 genome AF: 0.762 AC: 115848 AN: 152104 Hom.: 44684 Cov.: 32 AF XY: 0.763 AC XY: 56731 AN XY: 74356

Gnomad4 AFR AF: 0.631

Gnomad4 AMR AF: 0.739

Gnomad4 ASJ AF: 0.814

Gnomad4 EAS AF: 0.858

Gnomad4 SAS AF: 0.793

Gnomad4 FIN AF: 0.835

Gnomad4 NFE AF: 0.821

Gnomad4 OTH AF: 0.778

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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, criteria provided, single submitter	clinical testing	GeneDx	Oct 15, 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	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). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Autosomal dominant nonsyndromic hearing loss 20 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

- -

Baraitser-winter syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	3.1
Dann	Benign	0.94
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: rs1139405; hg19: chr17-79478019; COSMIC: COSV59509939; COSMIC: COSV59509939;