17-81510564-G-A

Variant names:

• chr17-81510564-G-A
• rs140458109
• ENST00000574671.6:n.1654C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001614.5(ACTG1):​c.*126C>T variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.0000128 in 1,096,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: ACTG1 NM_001614.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.10
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Baraitser-winter syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss 20

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Baraitser-Winter cerebrofrontofacial syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTG1	NM_001614.5	c.*126C>T		3_prime_UTR_variant	Exon 6 of 6	ENST00000573283.7	NP_001605.1
ACTG1	NR_037688.3	n.1326C>T		non_coding_transcript_exon_variant	Exon 6 of 7
ACTG1	NM_001199954.3	c.*126C>T		3_prime_UTR_variant	Exon 6 of 6		NP_001186883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTG1	ENST00000573283.7	c.*126C>T		3_prime_UTR_variant	Exon 6 of 6	5	NM_001614.5	ENSP00000458435.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000919 AC: 2 AN: 217604 AF XY: 0.00000841

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000210

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000128 AC: 14 AN: 1096188 Hom.: 0 Cov.: 15 AF XY: 0.0000161 AC XY: 9 AN XY: 560114

African (AFR) AF: 0.00 AC: 0 AN: 26152

American (AMR) AF: 0.00 AC: 0 AN: 40730

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23664

East Asian (EAS) AF: 0.0000267 AC: 1 AN: 37428

South Asian (SAS) AF: 0.0000129 AC: 1 AN: 77470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3498

European-Non Finnish (NFE) AF: 0.0000152 AC: 12 AN: 788056

Other (OTH) AF: 0.00 AC: 0 AN: 48164

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Benign	0.93
PhyloP100		5.1

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

Other links and lift over

dbSNP: rs140458109; hg19: chr17-79477590;