rs11549223

Positions:

chr17-81510690-T-C

Variant summary

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

The NM_001614.5(ACTG1):c.1128A>G(p.Ter376=) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.03

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 17-81510690-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/exons	MANE
ACTG1	NM_001614.5 linkuse as main transcript	c.1128A>G	p.Ter376=	stop_retained_variant	6/6	ENST00000573283.7
ACTG1	NM_001199954.3 linkuse as main transcript	c.1128A>G	p.Ter376=	stop_retained_variant	6/6
ACTG1	NR_037688.3 linkuse as main transcript	n.1200A>G		non_coding_transcript_exon_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTG1	ENST00000573283.7 linkuse as main transcript	c.1128A>G	p.Ter376=	stop_retained_variant	6/6	5	NM_001614.5	P4

Frequencies

GnomAD3 genomes

AF:

0.0403

AC:

6126

AN:

152160

Hom.:

226

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0163

AC XY:

11846

AN XY:

727142

show subpopulations

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.:

AF XY:

0.0399

AC XY:

2969

AN XY:

74454

show subpopulations

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.:

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

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 04, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 11, 2013	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) -
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. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.61

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

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