NM_004924.6:c.2670C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004924.6(ACTN4):c.2670C>A(p.Asp890Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,612,686 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D890D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0035 ( 5 hom., cov: 31)

Exomes 𝑓: 0.0011 ( 22 hom. )

Consequence

ACTN4
NM_004924.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.03

Publications

5 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074783266).

BP6

Variant 19-38729366-C-A is Benign according to our data. Variant chr19-38729366-C-A is described in ClinVar as Benign. ClinVar VariationId is 259577.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 = 0.0035 (532/152090) while in subpopulation AFR AF = 0.00933 (387/41494). AF 95% confidence interval is 0.00856. There are 5 homozygotes in GnomAd4. There are 254 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 532 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN4	NM_004924.6 link	c.2670C>A	p.Asp890Glu	missense_variant	Exon 21 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.2670C>A	p.Asp890Glu	missense_variant	Exon 21 of 21	1	NM_004924.6	ENSP00000252699.2		O43707-1

Frequencies

GnomAD3 genomes

AF:

0.00350

AC:

532

AN:

151972

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00935

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.0286

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00224

AC:

558

AN:

249208

AF XY:

0.00194

show subpopulations

Gnomad AFR exome

AF:

0.00956

Gnomad AMR exome

AF:

0.000550

Gnomad ASJ exome

AF:

0.0325

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000392

Gnomad OTH exome

AF:

0.00230

GnomAD4 exome

AF:

0.00111

AC:

1619

AN:

1460596

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

754

AN XY:

726620

show subpopulations

African (AFR)

AF:

0.0105

AC:

351

AN:

33480

American (AMR)

AF:

0.000559

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0330

AC:

862

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000197

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52214

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000160

AC:

178

AN:

1111976

Other (OTH)

AF:

0.00285

AC:

172

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

111

223

334

446

557

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00350

AC:

532

AN:

152090

Hom.:

Cov.:

AF XY:

0.00342

AC XY:

254

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.00933

AC:

387

AN:

41494

American (AMR)

AF:

0.000915

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0286

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.000623

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

67954

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

101

126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00181

Hom.:

Bravo

AF:

0.00380

ESP6500AA

AF:

0.00931

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00189

AC:

229

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 17, 2020

GeneDx

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

- -

Focal segmental glomerulosclerosis

Benign:1

Nov 18, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Focal segmental glomerulosclerosis 1

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

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Benign

0.062

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.40

T;.;T;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.26

MetaRNN

Benign

0.0075

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.1

M;.;.;.

PhyloP100

-1.0

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.5

N;N;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.19

T;T;T;T

Sift4G

Benign

0.48

T;T;T;T

Polyphen

0.0010

B;.;.;.

Vest4

0.49

MutPred

0.42

Loss of relative solvent accessibility (P = 0.107);.;.;.;

MVP

0.69

MPC

1.7

ClinPred

0.029

GERP RS

-7.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.12

gMVP

0.43

Mutation Taster

=88/12

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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