chr17-81510578-G-A

Variant names:

• chr17-81510578-G-A
• rs368494254
• ENST00000574671.6:n.1640C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001614.5(ACTG1):​c.*112C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,378,522 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (65 hom.)
• Consequence: ACTG1 NM_001614.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.332
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 17-81510578-G-A is Benign according to our data. Variant chr17-81510578-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1198354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00122 (186/152324) while in subpopulation SAS AF = 0.0329 (159/4830). AF 95% confidence interval is 0.0287. There are 5 homozygotes in GnomAd4. There are 132 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 186 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTG1	NM_001614.5	c.*112C>T		3_prime_UTR_variant	Exon 6 of 6	ENST00000573283.7	NP_001605.1
ACTG1	NR_037688.3	n.1312C>T		non_coding_transcript_exon_variant	Exon 6 of 7
ACTG1	NM_001199954.3	c.*112C>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.*112C>T		3_prime_UTR_variant	Exon 6 of 6	5	NM_001614.5	ENSP00000458435.1

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 152206 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0329

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00400 AC: 942 AN: 235458 AF XY: 0.00542

Gnomad AFR exome AF: 0.000146

Gnomad AMR exome AF: 0.000181

Gnomad ASJ exome AF: 0.00247

Gnomad EAS exome AF: 0.000459

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000487

Gnomad OTH exome AF: 0.00275

GnomAD4 exome AF: 0.00250 AC: 3068 AN: 1226198 Hom.: 65 Cov.: 17 AF XY: 0.00349 AC XY: 2164 AN XY: 620856

African (AFR) AF: 0.000175 AC: 5 AN: 28638

American (AMR) AF: 0.000162 AC: 7 AN: 43110

Ashkenazi Jewish (ASJ) AF: 0.00308 AC: 76 AN: 24646

East Asian (EAS) AF: 0.000130 AC: 5 AN: 38484

South Asian (SAS) AF: 0.0300 AC: 2437 AN: 81100

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52012

Middle Eastern (MID) AF: 0.00699 AC: 26 AN: 3722

European-Non Finnish (NFE) AF: 0.000408 AC: 368 AN: 902110

Other (OTH) AF: 0.00273 AC: 143 AN: 52376

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152324 Hom.: 5 Cov.: 32 AF XY: 0.00177 AC XY: 132 AN XY: 74490

African (AFR) AF: 0.000120 AC: 5 AN: 41564

American (AMR) AF: 0.000131 AC: 2 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0329 AC: 159 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68034

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000983 Hom.: 0

Bravo AF: 0.000404

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 28, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.0
DANN	Benign	0.91
PhyloP100		0.33
Mutation Taster		=100/0	polymorphism

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: rs368494254; hg19: chr17-79477604;