dbSNP rs2230158: ACTG1:p.Tyr133Tyr (chr17-81511591-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001614.5(ACTG1):c.399C>T(p.Tyr133Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,613,640 control chromosomes in the GnomAD database, including 260 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 28 hom., cov: 33)

Exomes 𝑓: 0.014 ( 232 hom. )

Consequence

ACTG1
NM_001614.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.00900

Publications

12 publications found

Variant links:

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, G2P, Labcorp Genetics (formerly Invitae)
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)
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Baraitser-Winter cerebrofrontofacial syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACTG1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 17-81511591-G-A is Benign according to our data. Variant chr17-81511591-G-A is described in ClinVar as Benign. ClinVar VariationId is 128270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.009 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0159 (2422/152338) while in subpopulation EAS AF = 0.0328 (170/5182). AF 95% confidence interval is 0.0288. There are 28 homozygotes in GnomAd4. There are 1196 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 2422 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACTG1	NM_001614.5	MANE Select	c.399C>T	p.Tyr133Tyr	synonymous	Exon 4 of 6	NP_001605.1	P63261
ACTG1	NM_001199954.3		c.399C>T	p.Tyr133Tyr	synonymous	Exon 4 of 6	NP_001186883.1	P63261
ACTG1	NR_037688.3		n.471C>T		non_coding_transcript_exon	Exon 4 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACTG1	ENST00000573283.7	TSL:5 MANE Select	c.399C>T	p.Tyr133Tyr	synonymous	Exon 4 of 6	ENSP00000458435.1	P63261
ACTG1	ENST00000575842.5	TSL:1	c.399C>T	p.Tyr133Tyr	synonymous	Exon 3 of 5	ENSP00000458162.1	P63261
ACTG1	ENST00000615544.5	TSL:1	c.399C>T	p.Tyr133Tyr	synonymous	Exon 4 of 6	ENSP00000477968.1	P63261

Frequencies

GnomAD3 genomes

AF:

0.0159

AC:

2420

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0158

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0212

Gnomad ASJ

AF:

0.0513

Gnomad EAS

AF:

0.0329

Gnomad SAS

AF:

0.0163

Gnomad FIN

AF:

0.00555

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0133

Gnomad OTH

AF:

0.0211

GnomAD2 exomes

AF:

0.0163

AC:

4088

AN:

250184

AF XY:

0.0160

show subpopulations

Gnomad AFR exome

AF:

0.0153

Gnomad AMR exome

AF:

0.0159

Gnomad ASJ exome

AF:

0.0486

Gnomad EAS exome

AF:

0.0303

Gnomad FIN exome

AF:

0.00624

Gnomad NFE exome

AF:

0.0131

Gnomad OTH exome

AF:

0.0194

GnomAD4 exome

AF:

0.0141

AC:

20660

AN:

1461302

Hom.:

232

Cov.:

AF XY:

0.0142

AC XY:

10339

AN XY:

726936

show subpopulations

African (AFR)

AF:

0.0160

AC:

537

AN:

33480

American (AMR)

AF:

0.0158

AC:

706

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0498

AC:

1301

AN:

26128

East Asian (EAS)

AF:

0.0225

AC:

892

AN:

39700

South Asian (SAS)

AF:

0.0169

AC:

1457

AN:

86248

European-Finnish (FIN)

AF:

0.00574

AC:

304

AN:

52950

Middle Eastern (MID)

AF:

0.0253

AC:

146

AN:

5768

European-Non Finnish (NFE)

AF:

0.0128

AC:

14193

AN:

1111934

Other (OTH)

AF:

0.0186

AC:

1124

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

1260

2521

3781

5042

6302

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

578

1156

1734

2312

2890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0159

AC:

2422

AN:

152338

Hom.:

Cov.:

AF XY:

0.0161

AC XY:

1196

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0159

AC:

659

AN:

41574

American (AMR)

AF:

0.0212

AC:

325

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0513

AC:

178

AN:

3472

East Asian (EAS)

AF:

0.0328

AC:

170

AN:

5182

South Asian (SAS)

AF:

0.0161

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00555

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0133

AC:

902

AN:

68036

Other (OTH)

AF:

0.0213

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

123

246

369

492

615

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0163

Hom.:

Bravo

AF:

0.0167

Asia WGS

AF:

0.0360

AC:

124

AN:

3478

EpiCase

AF:

0.0161

EpiControl

AF:

0.0156

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (4)

Autosomal dominant nonsyndromic hearing loss 20 (1)

Autosomal dominant nonsyndromic hearing loss 20;C3281235:Baraitser-winter syndrome 2 (1)

Baraitser-winter syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_noAF

Benign

-0.51

CADD

Benign

8.1

(source)

DANN

Benign

0.94

PhyloP100

-0.0090

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over