rs11546939

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_001101.5(ACTB):c.942G>A(p.Gln314Gln) variant causes a synonymous change. The variant allele was found at a frequency of 0.0315 in 1,614,222 control chromosomes in the GnomAD database, including 917 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 86 hom., cov: 33)

Exomes 𝑓: 0.031 ( 831 hom. )

Consequence

ACTB
NM_001101.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.78

Publications

12 publications found

Variant links:

Genes affected

ACTB (HGNC:132): (actin beta) This gene encodes one of six different actin proteins. Actins are highly conserved proteins that are involved in cell motility, structure, integrity, and intercellular signaling. The encoded protein is a major constituent of the contractile apparatus and one of the two nonmuscle cytoskeletal actins that are ubiquitously expressed. Mutations in this gene cause Baraitser-Winter syndrome 1, which is characterized by intellectual disability with a distinctive facial appearance in human patients. Numerous pseudogenes of this gene have been identified throughout the human genome. [provided by RefSeq, Aug 2017]

ACTB Gene-Disease associations (from GenCC):

Baraitser-Winter cerebrofrontofacial syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Baraitser-Winter syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia, G2P
developmental malformations-deafness-dystonia syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Illumina
ACTB-associated syndromic thrombocytopenia
Inheritance: AD Classification: MODERATE Submitted by: ClinGen, Ambry Genetics

ACTB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 7-5528046-C-T is Benign according to our data. Variant chr7-5528046-C-T is described in ClinVar as Benign. ClinVar VariationId is 128264.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 = 0.0332 (5050/152334) while in subpopulation AFR AF = 0.0442 (1838/41568). AF 95% confidence interval is 0.0425. There are 86 homozygotes in GnomAd4. There are 2349 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 5050 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTB	NM_001101.5 link	c.942G>A	p.Gln314Gln	synonymous_variant	Exon 5 of 6	ENST00000646664.1	NP_001092.1	P60709Q1KLZ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTB	ENST00000646664.1 link	c.942G>A	p.Gln314Gln	synonymous_variant	Exon 5 of 6		NM_001101.5	ENSP00000494750.1		P60709

Frequencies

GnomAD3 genomes

AF:

0.0332

AC:

5049

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0443

Gnomad AMI

AF:

0.0527

Gnomad AMR

AF:

0.0280

Gnomad ASJ

AF:

0.0541

Gnomad EAS

AF:

0.0117

Gnomad SAS

AF:

0.0227

Gnomad FIN

AF:

0.0120

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0318

Gnomad OTH

AF:

0.0330

GnomAD2 exomes

AF:

0.0278

AC:

6980

AN:

251474

AF XY:

0.0287

show subpopulations

Gnomad AFR exome

AF:

0.0425

Gnomad AMR exome

AF:

0.0193

Gnomad ASJ exome

AF:

0.0512

Gnomad EAS exome

AF:

0.0135

Gnomad FIN exome

AF:

0.0114

Gnomad NFE exome

AF:

0.0313

Gnomad OTH exome

AF:

0.0336

GnomAD4 exome

AF:

0.0314

AC:

45850

AN:

1461888

Hom.:

831

Cov.:

AF XY:

0.0312

AC XY:

22703

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0474

AC:

1587

AN:

33480

American (AMR)

AF:

0.0203

AC:

910

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0533

AC:

1394

AN:

26136

East Asian (EAS)

AF:

0.0130

AC:

515

AN:

39700

South Asian (SAS)

AF:

0.0288

AC:

2483

AN:

86258

European-Finnish (FIN)

AF:

0.0120

AC:

641

AN:

53420

Middle Eastern (MID)

AF:

0.0442

AC:

255

AN:

5768

European-Non Finnish (NFE)

AF:

0.0325

AC:

36164

AN:

1112006

Other (OTH)

AF:

0.0315

AC:

1901

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

3644

7288

10932

14576

18220

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1416

2832

4248

5664

7080

<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:

0.0332

AC:

5050

AN:

152334

Hom.:

Cov.:

AF XY:

0.0315

AC XY:

2349

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.0442

AC:

1838

AN:

41568

American (AMR)

AF:

0.0280

AC:

428

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0541

AC:

188

AN:

3472

East Asian (EAS)

AF:

0.0117

AC:

AN:

5192

South Asian (SAS)

AF:

0.0225

AC:

109

AN:

4834

European-Finnish (FIN)

AF:

0.0120

AC:

127

AN:

10622

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0318

AC:

2163

AN:

68034

Other (OTH)

AF:

0.0326

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

243

486

729

972

1215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<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:

0.0351

Hom.:

Bravo

AF:

0.0350

Asia WGS

AF:

0.0250

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Nov 05, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Mar 03, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 27, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Gln314Gln in exon 5 of ACTB: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 4.36% (454/10402) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs11546939). -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Baraitser-Winter syndrome 1

Benign:3

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

African/African American population allele frequency is 3.989% (rs11546939,1081/24968 alleles, 22 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.2.1, this variant is classified as BENIGN. Following criteria are met: BA1 -

Developmental malformations-deafness-dystonia syndrome

Benign:1

Dec 05, 2021

Genome-Nilou Lab

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

-0.44

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

4.8

PromoterAI

-0.036

Neutral

(source)

Mutation Taster

=31/69

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over