rs140724578

Positions:

• chr17-81512363-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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

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 -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	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTG1	NM_001614.5	c.-6-3C>T		splice_region_variant, intron_variant		ENST00000573283.7	NP_001605.1
ACTG1	NM_001199954.3	c.-6-3C>T		splice_region_variant, intron_variant			NP_001186883.1
ACTG1	NR_037688.3	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	c.-6-3C>T		splice_region_variant, intron_variant		5	NM_001614.5	ENSP00000458435.1

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 573 AN: 152188 Hom.: 2 Cov.: 32

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.: 4 AF XY: 0.00414 AC XY: 563 AN XY: 135870

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.: 26 Cov.: 37 AF XY: 0.00494 AC XY: 3594 AN XY: 727132

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.: 2 Cov.: 32 AF XY: 0.00330 AC XY: 246 AN XY: 74474

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.: 2

Bravo AF: 0.00394

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

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

Other links and lift over

dbSNP: rs140724578; hg19: chr17-79479389;