rs781801921

Variant names:

• chr17-81512355-T-C
• rs781801921
• ENST00000574671.6:n.124A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-81512355-T-C
• chr17-81512355-T-G

Variant summary

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

The ENST00000574671.6(ACTG1):​n.124A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,613,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: ACTG1 ENST00000574671.6 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.841
• 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=-0.45).
• BS2: High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTG1	NM_001614.5	c.-1A>G		5_prime_UTR_variant	Exon 2 of 6	ENST00000573283.7	NP_001605.1
ACTG1	NR_037688.3	n.72A>G		non_coding_transcript_exon_variant	Exon 2 of 7
ACTG1	NM_001199954.3	c.-1A>G		5_prime_UTR_variant	Exon 2 of 6		NP_001186883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTG1	ENST00000573283.7	c.-1A>G		5_prime_UTR_variant	Exon 2 of 6	5	NM_001614.5	ENSP00000458435.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000836 AC: 21 AN: 251316 AF XY: 0.0000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000142 AC: 207 AN: 1461668 Hom.: 0 Cov.: 37 AF XY: 0.000127 AC XY: 92 AN XY: 727160

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000179 AC: 199 AN: 1111916

Other (OTH) AF: 0.0000662 AC: 4 AN: 60386

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74310

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.0000718

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Jun 09, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-1A>G variant in ACTG1 has not been previously reported in individuals wit h with hearing loss or Baraitser-Winter syndrome. This variant has been identifi ed in 8/66460 European chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs781801921). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant is located in the 5'UTR at the -1 nucleotide posit ion, which is not conserved across species including mammals. Computational tool s do not suggest an impact to splicing. However, this information is not predict ive enough to rule out pathogenicity. In summary, the clinical significance of t he c.-1A>G variant is uncertain. -

Nov 13, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ACTG1 c.-1A>G is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 8.4e-05 in 251316 control chromosomes (gnomAD). To our knowledge, no occurrence of c.-1A>G in individuals affected with ACTG1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 505118). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	2.3
DANN	Benign	0.58
PhyloP100		-0.84
PromoterAI		-0.054	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs781801921; hg19: chr17-79479381;