rs201748657

chr17-81511634-G-Achr17-81511634-G-C

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.364-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,612,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: ACTG1 NM_001614.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003194
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0220

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=-0.87).
• BP6: Variant 17-81511634-G-A is Benign according to our data. Variant chr17-81511634-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 180117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-81511634-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000302 (46/152356) while in subpopulation AMR AF= 0.00196 (30/15312). AF 95% confidence interval is 0.00141. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTG1	NM_001614.5	c.364-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000573283.7
ACTG1	NM_001199954.3	c.364-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ACTG1	NR_037688.3	n.436-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTG1	ENST00000573283.7	c.364-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001614.5	P4

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.0000807 AC: 20 AN: 247844 Hom.: 0 AF XY: 0.0000744 AC XY: 10 AN XY: 134488

Gnomad AFR exome AF: 0.000255

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000986

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000836 AC: 122 AN: 1459892 Hom.: 0 Cov.: 37 AF XY: 0.0000909 AC XY: 66 AN XY: 726248

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000269

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000828

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74502

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.0000660 Hom.: 0

Bravo AF: 0.000563

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 06, 2014

c.364-8C>T in intron 3 of ACTG1: This variant is not expected to have clinical s ignificance because a C>T change at this position does not diverge from the spli ce consensus sequence and is therefore unlikely to impact splicing. It has been identified in 0.9% (1/110) of Puerto Ricans by the 1000 genomes Project and has been reported in 3/9738 African chromosomes and 4/64902 European chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org; dbSNP rs201748 657). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 03, 2020

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2023

- -

ACTG1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 26, 2021

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.1
Dann	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.066
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: rs201748657; hg19: chr17-79478660;