ENST00000574671.6:n.1654C>A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000574671.6(ACTG1):​n.1654C>A variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.00000274 in 1,096,180 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: 0.0000027 (0 hom.)
• Consequence: ACTG1 ENST00000574671.6 non_coding_transcript_exon
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTG1	NM_001614.5	c.*126C>A		3_prime_UTR_variant	Exon 6 of 6	ENST00000573283.7	NP_001605.1
ACTG1	NR_037688.3	n.1326C>A		non_coding_transcript_exon_variant	Exon 6 of 7
ACTG1	NM_001199954.3	c.*126C>A		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>A		3_prime_UTR_variant	Exon 6 of 6	5	NM_001614.5	ENSP00000458435.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1096180 Hom.: 0 Cov.: 15 AF XY: 0.00000357 AC XY: 2 AN XY: 560106

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 0.00 AC: 0 AN: 37428

South Asian (SAS) AF: 0.00 AC: 0 AN: 77470

European-Finnish (FIN) AF: 0.0000196 AC: 1 AN: 51026

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

European-Non Finnish (NFE) AF: 0.00000254 AC: 2 AN: 788048

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000065), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
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;