rs11549223

Variant names:

• chr17-81510690-T-C
• rs11549223
• NM_001614.5:c.1128A>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.1128A>G​(p.Ter376Ter) variant causes a stop retained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,613,942 control chromosomes in the GnomAD database, including 640 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (224 hom., cov: 32)
  • Exomes 𝑓: 0.017 (416 hom.)
• Consequence: ACTG1 NM_001614.5 stop_retained
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.03

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=-0.61).
• BP6: Variant 17-81510690-T-C is Benign according to our data. Variant chr17-81510690-T-C is described in ClinVar as [Benign]. Clinvar id is 128269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-81510690-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.03 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.098 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTG1	NM_001614.5	c.1128A>G	p.Ter376Ter	stop_retained_variant	Exon 6 of 6	ENST00000573283.7	NP_001605.1
ACTG1	NM_001199954.3	c.1128A>G	p.Ter376Ter	stop_retained_variant	Exon 6 of 6		NP_001186883.1
ACTG1	NR_037688.3	n.1200A>G		non_coding_transcript_exon_variant	Exon 6 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTG1	ENST00000573283.7	c.1128A>G	p.Ter376Ter	stop_retained_variant	Exon 6 of 6	5	NM_001614.5	ENSP00000458435.1

Frequencies

GnomAD3 genomes AF: 0.0403 AC: 6126 AN: 152160 Hom.: 226 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0300

Gnomad ASJ AF: 0.0513

Gnomad EAS AF: 0.0331

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.00556

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.0411

GnomAD3 exomes AF: 0.0225 AC: 5654 AN: 251408 Hom.: 139 AF XY: 0.0208 AC XY: 2827 AN XY: 135906

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.0194

Gnomad ASJ exome AF: 0.0486

Gnomad EAS exome AF: 0.0303

Gnomad SAS exome AF: 0.0170

Gnomad FIN exome AF: 0.00637

Gnomad NFE exome AF: 0.0134

Gnomad OTH exome AF: 0.0212

GnomAD4 exome AF: 0.0165 AC: 24139 AN: 1461664 Hom.: 416 Cov.: 30 AF XY: 0.0163 AC XY: 11846 AN XY: 727142

Gnomad4 AFR exome AF: 0.0991

Gnomad4 AMR exome AF: 0.0199

Gnomad4 ASJ exome AF: 0.0499

Gnomad4 EAS exome AF: 0.0228

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: 0.0403 AC: 6135 AN: 152278 Hom.: 224 Cov.: 32 AF XY: 0.0399 AC XY: 2969 AN XY: 74454

Gnomad4 AFR AF: 0.100

Gnomad4 AMR AF: 0.0300

Gnomad4 ASJ AF: 0.0513

Gnomad4 EAS AF: 0.0330

Gnomad4 SAS AF: 0.0170

Gnomad4 FIN AF: 0.00556

Gnomad4 NFE AF: 0.0135

Gnomad4 OTH AF: 0.0411

Alfa AF: 0.0245 Hom.: 76

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Apr 11, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

X376X in exon 6 of ACTG1: This variant is not expected to have clinical signific ance because it does not alter the termination codon, it is not located within t he splice consensus sequence, it has been identified in 1.3% (113/8600) of Europ ean American chromosomes and 9% (395/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washingt on.edu/EVS/; dbSNP rs11549223) -

Mar 04, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 13, 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. -

not provided Benign:2

May 23, 2018

Athena Diagnostics

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

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Baraitser-winter syndrome 2 Benign:1

Dec 05, 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 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	7.5
DANN	Benign	0.72
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: rs11549223; hg19: chr17-79477716; COSMIC: COSV59509925; COSMIC: COSV59509925;