rs143978597

Variant names:

• chr17-81511576-G-A
• rs143978597
• NM_001614.5:c.414C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-81511576-G-A
• chr17-81511576-G-C
• chr17-81511576-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001614.5(ACTG1):​c.414C>T​(p.Ala138Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000439 in 1,613,820 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00043 (7 hom.)
• Consequence: ACTG1 NM_001614.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -4.39

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=-0.8).
• BP6: Variant 17-81511576-G-A is Benign according to our data. Variant chr17-81511576-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-81511576-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.39 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000525 (80/152378) while in subpopulation AFR AF= 0.000649 (27/41592). AF 95% confidence interval is 0.000458. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 80 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTG1	NM_001614.5	c.414C>T	p.Ala138Ala	synonymous_variant	Exon 4 of 6	ENST00000573283.7	NP_001605.1
ACTG1	NM_001199954.3	c.414C>T	p.Ala138Ala	synonymous_variant	Exon 4 of 6		NP_001186883.1
ACTG1	NR_037688.3	n.486C>T		non_coding_transcript_exon_variant	Exon 4 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTG1	ENST00000573283.7	c.414C>T	p.Ala138Ala	synonymous_variant	Exon 4 of 6	5	NM_001614.5	ENSP00000458435.1

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 81 AN: 152260 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000411

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000559 AC: 140 AN: 250458 Hom.: 0 AF XY: 0.000627 AC XY: 85 AN XY: 135632

Gnomad AFR exome AF: 0.000437

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00219

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000513

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000430 AC: 629 AN: 1461442 Hom.: 7 Cov.: 37 AF XY: 0.000476 AC XY: 346 AN XY: 727018

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00191

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00132

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000247

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000525 AC: 80 AN: 152378 Hom.: 0 Cov.: 33 AF XY: 0.000483 AC XY: 36 AN XY: 74518

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000359 Hom.: 0

Bravo AF: 0.000544

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACTG1: BP4, BP7 -

Feb 28, 2018

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 specified Benign:2

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ala138Ala in Exon 04 of ACTG1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 0.1% (3/3738) of Afri can American chromosomes from a broad population by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS; dbSNP rs143978597). -

Jul 23, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

ACTG1-related disorder Benign:1

May 07, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autosomal dominant nonsyndromic hearing loss 20;C3281235:Baraitser-winter syndrome 2 Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.1
DANN	Benign	0.91

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: rs143978597; hg19: chr17-79478602;