rs28478053

Variant names:

• chr17-81510556-G-A
• rs28478053
• NM_001614.5:c.*134C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-81510556-G-A
• chr17-81510556-G-C

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.*134C>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 0.00291 in 1,169,086 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (36 hom.)
• Consequence: ACTG1 NM_001614.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.54
• Publications: 2 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, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• nonsyndromic genetic hearing loss

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

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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 17-81510556-G-A is Benign according to our data. Variant chr17-81510556-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1198803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0125 (1902/152332) while in subpopulation AFR AF = 0.042 (1745/41580). AF 95% confidence interval is 0.0403. There are 41 homozygotes in GnomAd4. There are 885 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1902 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001614.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTG1	NM_001614.5	MANE Select	c.*134C>T		3_prime_UTR	Exon 6 of 6	NP_001605.1	P63261
	ACTG1	NM_001199954.3		c.*134C>T		3_prime_UTR	Exon 6 of 6	NP_001186883.1	P63261
	ACTG1	NR_037688.3		n.1334C>T		non_coding_transcript_exon	Exon 6 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTG1	ENST00000573283.7	TSL:5 MANE Select	c.*134C>T		3_prime_UTR	Exon 6 of 6	ENSP00000458435.1	P63261
	ACTG1	ENST00000575842.5	TSL:1	c.*134C>T		3_prime_UTR	Exon 5 of 5	ENSP00000458162.1	P63261
	ACTG1	ENST00000615544.5	TSL:1	c.*134C>T		3_prime_UTR	Exon 6 of 6	ENSP00000477968.1	P63261

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1886 AN: 152214 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.0417

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00772

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00289 AC: 584 AN: 202260 AF XY: 0.00218

Gnomad AFR exome AF: 0.0449

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.00209

GnomAD4 exome AF: 0.00148 AC: 1504 AN: 1016754 Hom.: 36 Cov.: 13 AF XY: 0.00128 AC XY: 667 AN XY: 522482

African (AFR) AF: 0.0443 AC: 1089 AN: 24608

American (AMR) AF: 0.00253 AC: 98 AN: 38720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23066

East Asian (EAS) AF: 0.00 AC: 0 AN: 36512

South Asian (SAS) AF: 0.0000133 AC: 1 AN: 75024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49876

Middle Eastern (MID) AF: 0.00208 AC: 7 AN: 3370

European-Non Finnish (NFE) AF: 0.000203 AC: 146 AN: 720056

Other (OTH) AF: 0.00358 AC: 163 AN: 45522

GnomAD4 genome AF: 0.0125 AC: 1902 AN: 152332 Hom.: 41 Cov.: 32 AF XY: 0.0119 AC XY: 885 AN XY: 74486

African (AFR) AF: 0.0420 AC: 1745 AN: 41580

American (AMR) AF: 0.00771 AC: 118 AN: 15296

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

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68028

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.00649 Hom.: 6

Bravo AF: 0.0149

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Benign	0.90
PhyloP100		2.5
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: rs28478053; hg19: chr17-79477582;