rs113969422

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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 (★★).

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

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 links:

ACTN4 (HGNC:):

ACTN4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTN4. . Gene score misZ 4.1552 (greater than the threshold 3.09). Trascript score misZ 5.6825 (greater than threshold 3.09). GenCC has associacion of gene with familial idiopathic steroid-resistant nephrotic syndrome, focal segmental glomerulosclerosis 1.

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 id 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 532 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTN4	NM_004924.6 linkuse as main transcript	c.2670C>A	p.Asp890Glu	missense_variant	21/21	ENST00000252699.7	NP_004915.2	O43707-1A0A0S2Z3G9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7 linkuse as main transcript	c.2670C>A	p.Asp890Glu	missense_variant	21/21	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

GnomAD3 exomes

AF:

0.00224

AC:

558

AN:

249208

Hom.:

AF XY:

0.00194

AC XY:

263

AN XY:

135436

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 SAS exome

AF:

0.000131

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

Gnomad4 AFR exome

AF:

0.0105

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.0330

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000160

Gnomad4 OTH exome

AF:

0.00285

GnomAD4 genome

AF:

0.00350

AC:

532

AN:

152090

Hom.:

Cov.:

AF XY:

0.00342

AC XY:

254

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00933

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.0286

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00182

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 21, 2023	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Focal segmental glomerulosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 18, 2020

- -

Focal segmental glomerulosclerosis 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

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

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;.;.;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over