dbSNP rs139517777: ACTG1:p.Asp24Asp (chr17-81512283-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.72C>T(p.Asp24Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000794 in 1,613,780 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00077 ( 2 hom. )

Consequence

ACTG1
NM_001614.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.366

Publications

0 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:

Genome browser will be placed here

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=-0.52).

BP6

Variant 17-81512283-G-A is Benign according to our data. Variant chr17-81512283-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.366 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00104 (159/152214) while in subpopulation AFR AF = 0.00233 (97/41552). AF 95% confidence interval is 0.00196. There are 0 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 159 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.72C>T	p.Asp24Asp	synonymous	Exon 2 of 6	NP_001605.1	P63261
ACTG1	NM_001199954.3		c.72C>T	p.Asp24Asp	synonymous	Exon 2 of 6	NP_001186883.1	P63261
ACTG1	NR_037688.3		n.144C>T		non_coding_transcript_exon	Exon 2 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACTG1	ENST00000573283.7	TSL:5 MANE Select	c.72C>T	p.Asp24Asp	synonymous	Exon 2 of 6	ENSP00000458435.1	P63261
ACTG1	ENST00000575842.5	TSL:1	c.72C>T	p.Asp24Asp	synonymous	Exon 1 of 5	ENSP00000458162.1	P63261
ACTG1	ENST00000615544.5	TSL:1	c.72C>T	p.Asp24Asp	synonymous	Exon 2 of 6	ENSP00000477968.1	P63261

Frequencies

GnomAD3 genomes

AF:

0.00102

AC:

155

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00224

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000545

AC:

137

AN:

251190

AF XY:

0.000545

show subpopulations

Gnomad AFR exome

AF:

0.00271

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000458

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000768

AC:

1122

AN:

1461566

Hom.:

Cov.:

AF XY:

0.000729

AC XY:

530

AN XY:

727116

show subpopulations

African (AFR)

AF:

0.00197

AC:

AN:

33478

American (AMR)

AF:

0.000201

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00107

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000376

AC:

AN:

53186

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000831

AC:

924

AN:

1111948

Other (OTH)

AF:

0.000397

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

162

244

325

406

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

126

168

210

<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:

0.00104

AC:

159

AN:

152214

Hom.:

Cov.:

AF XY:

0.000968

AC XY:

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.00233

AC:

AN:

41552

American (AMR)

AF:

0.000327

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00145

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000735

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000853

Hom.:

Bravo

AF:

0.00110

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000296

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (3)

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

BayesDel_noAF

Benign

-0.52

CADD

Benign

6.1

(source)

DANN

Benign

0.90

PhyloP100

-0.37

PromoterAI

0.033

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

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

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