rs12986337

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004924.6(ACTN4):c.1977T>C(p.Asn659Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.065 in 1,613,590 control chromosomes in the GnomAD database, including 3,757 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.057 ( 265 hom., cov: 32)

Exomes 𝑓: 0.066 ( 3492 hom. )

Consequence

ACTN4
NM_004924.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.00600

Publications

12 publications found

Variant links:

Genes affected

ACTN4 (HGNC:166): (actinin alpha 4) Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a nonmuscle, alpha actinin isoform which is concentrated in the cytoplasm, and thought to be involved in metastatic processes. Mutations in this gene have been associated with focal and segmental glomerulosclerosis. [provided by RefSeq, Jul 2008]

ACTN4 Gene-Disease associations (from GenCC):

focal segmental glomerulosclerosis 1
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACTN4 links:

ENSG00000298338 (HGNC:):

ENSG00000298338 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=-0.77).

BP6

Variant 19-38724532-T-C is Benign according to our data. Variant chr19-38724532-T-C is described in ClinVar as Benign. ClinVar VariationId is 259571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.006 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0889 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN4	NM_004924.6 link	c.1977T>C	p.Asn659Asn	synonymous_variant	Exon 16 of 21	ENST00000252699.7	NP_004915.2	O43707-1A0A0S2Z3G9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7 link	c.1977T>C	p.Asn659Asn	synonymous_variant	Exon 16 of 21	1	NM_004924.6	ENSP00000252699.2		O43707-1

Frequencies

GnomAD3 genomes

AF:

0.0572

AC:

8693

AN:

152084

Hom.:

266

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0502

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0617

Gnomad ASJ

AF:

0.0582

Gnomad EAS

AF:

0.0460

Gnomad SAS

AF:

0.0967

Gnomad FIN

AF:

0.0259

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0638

Gnomad OTH

AF:

0.0578

GnomAD2 exomes

AF:

0.0635

AC:

15909

AN:

250450

AF XY:

0.0651

show subpopulations

Gnomad AFR exome

AF:

0.0509

Gnomad AMR exome

AF:

0.0698

Gnomad ASJ exome

AF:

0.0615

Gnomad EAS exome

AF:

0.0405

Gnomad FIN exome

AF:

0.0279

Gnomad NFE exome

AF:

0.0628

Gnomad OTH exome

AF:

0.0679

GnomAD4 exome

AF:

0.0659

AC:

96234

AN:

1461388

Hom.:

3492

Cov.:

AF XY:

0.0668

AC XY:

48593

AN XY:

727006

show subpopulations

African (AFR)

AF:

0.0518

AC:

1734

AN:

33472

American (AMR)

AF:

0.0729

AC:

3258

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0632

AC:

1651

AN:

26128

East Asian (EAS)

AF:

0.0457

AC:

1815

AN:

39698

South Asian (SAS)

AF:

0.102

AC:

8761

AN:

86254

European-Finnish (FIN)

AF:

0.0305

AC:

1616

AN:

53016

Middle Eastern (MID)

AF:

0.0687

AC:

396

AN:

5766

European-Non Finnish (NFE)

AF:

0.0657

AC:

73010

AN:

1111952

Other (OTH)

AF:

0.0661

AC:

3993

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

6894

13789

20683

27578

34472

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2804

5608

8412

11216

14020

<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:

0.0571

AC:

8697

AN:

152202

Hom.:

265

Cov.:

AF XY:

0.0563

AC XY:

4194

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0502

AC:

2083

AN:

41522

American (AMR)

AF:

0.0615

AC:

942

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0582

AC:

202

AN:

3470

East Asian (EAS)

AF:

0.0461

AC:

239

AN:

5180

South Asian (SAS)

AF:

0.0961

AC:

464

AN:

4826

European-Finnish (FIN)

AF:

0.0259

AC:

274

AN:

10588

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0638

AC:

4341

AN:

67988

Other (OTH)

AF:

0.0587

AC:

124

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

451

902

1353

1804

2255

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

208

312

416

520

<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:

0.0595

Hom.:

116

Bravo

AF:

0.0594

Asia WGS

AF:

0.0890

AC:

311

AN:

3478

EpiCase

AF:

0.0649

EpiControl

AF:

0.0670

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Focal segmental glomerulosclerosis 1

Benign:2

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 12, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

-0.77

CADD

Benign

6.1

(source)

DANN

Benign

0.61

PhyloP100

0.0060

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

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