rs11549165

Variant names:

• chr17-81510544-T-C
• rs11549165
• ENST00000574671.6:n.1674A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001614.5(ACTG1):​c.*146A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000474 in 1,010,986 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: ACTG1 NM_001614.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.232
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 17-81510544-T-C is Benign according to our data. Variant chr17-81510544-T-C is described in ClinVar as [Benign]. Clinvar id is 1272876.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00188 (286/152372) while in subpopulation AFR AF = 0.00642 (267/41590). AF 95% confidence interval is 0.00579. There are 2 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 286 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTG1	NM_001614.5	c.*146A>G		3_prime_UTR_variant	Exon 6 of 6	ENST00000573283.7	NP_001605.1
ACTG1	NR_037688.3	n.1346A>G		non_coding_transcript_exon_variant	Exon 6 of 7
ACTG1	NM_001199954.3	c.*146A>G		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.*146A>G		3_prime_UTR_variant	Exon 6 of 6	5	NM_001614.5	ENSP00000458435.1

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 286 AN: 152254 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00644

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000354 AC: 65 AN: 183754 AF XY: 0.000270

Gnomad AFR exome AF: 0.00606

Gnomad AMR exome AF: 0.000186

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000202

GnomAD4 exome AF: 0.000225 AC: 193 AN: 858614 Hom.: 0 Cov.: 12 AF XY: 0.000192 AC XY: 86 AN XY: 447032

African (AFR) AF: 0.00770 AC: 165 AN: 21422

American (AMR) AF: 0.000299 AC: 11 AN: 36836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21914

East Asian (EAS) AF: 0.00 AC: 0 AN: 34936

South Asian (SAS) AF: 0.0000141 AC: 1 AN: 70970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3062

European-Non Finnish (NFE) AF: 0.00000861 AC: 5 AN: 580896

Other (OTH) AF: 0.000273 AC: 11 AN: 40220

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152372 Hom.: 2 Cov.: 32 AF XY: 0.00195 AC XY: 145 AN XY: 74506

African (AFR) AF: 0.00642 AC: 267 AN: 41590

American (AMR) AF: 0.000849 AC: 13 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000278 Hom.: 0

Bravo AF: 0.00221

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 06, 2020

GeneDx

Significance: 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	-0.56
CADD	Benign	11
DANN	Benign	0.85
PhyloP100		-0.23
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: rs11549165; hg19: chr17-79477570;