17-81512363-G-A

Position:

chr17-81512363-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001614.5(ACTG1):c.-6-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00488 in 1,613,926 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 26 hom. )

Consequence

ACTG1
NM_001614.5 splice_region, intron

Scores

Splicing: ADA: 0.002434

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.922

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 17-81512363-G-A is Benign according to our data. Variant chr17-81512363-G-A is described in ClinVar as [Benign]. Clinvar id is 226457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-81512363-G-A is described in Lovd as [Benign]. Variant chr17-81512363-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00376 (573/152306) while in subpopulation NFE AF= 0.00648 (441/68032). AF 95% confidence interval is 0.00598. There are 2 homozygotes in gnomad4. There are 246 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 573 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
ACTG1	NM_001614.5 link	c.-6-3C>T	splice_region_variant, intron_variant	ENST00000573283.7	NP_001605.1	P63261
ACTG1	NM_001199954.3 link	c.-6-3C>T	splice_region_variant, intron_variant		NP_001186883.1	P63261
ACTG1	NR_037688.3 link	n.67-3C>T	splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTG1	ENST00000573283.7 link	c.-6-3C>T		splice_region_variant, intron_variant		5	NM_001614.5	ENSP00000458435.1		P63261

Frequencies

GnomAD3 genomes

AF:

0.00377

AC:

573

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00648

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00401

AC:

1008

AN:

251284

Hom.:

AF XY:

0.00414

AC XY:

563

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.000924

Gnomad AMR exome

AF:

0.00249

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00265

Gnomad FIN exome

AF:

0.00231

Gnomad NFE exome

AF:

0.00637

Gnomad OTH exome

AF:

0.00571

GnomAD4 exome

AF:

0.00500

AC:

7310

AN:

1461620

Hom.:

Cov.:

AF XY:

0.00494

AC XY:

3594

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.000866

Gnomad4 AMR exome

AF:

0.00306

Gnomad4 ASJ exome

AF:

0.00161

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00271

Gnomad4 FIN exome

AF:

0.00220

Gnomad4 NFE exome

AF:

0.00582

Gnomad4 OTH exome

AF:

0.00427

GnomAD4 genome

AF:

0.00376

AC:

573

AN:

152306

Hom.:

Cov.:

AF XY:

0.00330

AC XY:

246

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000866

Gnomad4 AMR

AF:

0.00301

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00226

Gnomad4 NFE

AF:

0.00648

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.00481

Hom.:

Bravo

AF:

0.00394

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2016	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	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ACTG1: BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	-6-3C>T in Intron 01 of ACTG1: This variant is not expected to have clinical sig nificance because it has been identified in 0.6% (42/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washin -

Autosomal dominant nonsyndromic hearing loss 20

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

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

-0.48

CADD

Benign

3.1

DANN

Benign

0.92

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0024

dbscSNV1_RF

Benign

0.062

SpliceAI score (max)

0.010

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