chr19-38723993-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_004924.6(ACTN4):c.1608C>T(p.Arg536Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00302 in 1,613,830 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 28 hom. )

Consequence

ACTN4
NM_004924.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.275

Publications

2 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 19-38723993-C-T is Benign according to our data. Variant chr19-38723993-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.275 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00253 (385/152220) while in subpopulation AMR AF = 0.0036 (55/15294). AF 95% confidence interval is 0.00284. There are 2 homozygotes in GnomAd4. There are 199 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 385 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN4	NM_004924.6 link	c.1608C>T	p.Arg536Arg	synonymous_variant	Exon 14 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.1608C>T	p.Arg536Arg	synonymous_variant	Exon 14 of 21	1	NM_004924.6	ENSP00000252699.2		O43707-1

Frequencies

GnomAD3 genomes

AF:

0.00254

AC:

386

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.0156

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.00312

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00359

AC:

902

AN:

251208

AF XY:

0.00383

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00286

Gnomad ASJ exome

AF:

0.0175

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00373

Gnomad OTH exome

AF:

0.00554

GnomAD4 exome

AF:

0.00308

AC:

4496

AN:

1461610

Hom.:

Cov.:

AF XY:

0.00330

AC XY:

2396

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.000896

AC:

AN:

33480

American (AMR)

AF:

0.00342

AC:

153

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0175

AC:

457

AN:

26134

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.00519

AC:

448

AN:

86258

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

53150

Middle Eastern (MID)

AF:

0.0494

AC:

285

AN:

5768

European-Non Finnish (NFE)

AF:

0.00250

AC:

2776

AN:

1112002

Other (OTH)

AF:

0.00558

AC:

337

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

314

628

942

1256

1570

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

200

300

400

500

<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:

0.00253

AC:

385

AN:

152220

Hom.:

Cov.:

AF XY:

0.00267

AC XY:

199

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.000458

AC:

AN:

41516

American (AMR)

AF:

0.00360

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00352

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00312

AC:

212

AN:

68008

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

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:

0.00411

Hom.:

Bravo

AF:

0.00257

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00529

EpiControl

AF:

0.00563

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Apr 14, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACTN4: BP4, BP7, BS2 -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 13, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

May 06, 2022

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

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

- -

Aug 03, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Focal segmental glomerulosclerosis

Benign:1

Jul 23, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

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

-0.33

CADD

Benign

(source)

DANN

Benign

0.53

PhyloP100

0.28

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over