rs3745859

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_004924.6(ACTN4):c.546C>T(p.Asn182Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,613,490 control chromosomes in the GnomAD database, including 169,091 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 12552 hom., cov: 32)

Exomes 𝑓: 0.46 ( 156539 hom. )

Consequence

ACTN4
NM_004924.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.54

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:

LOC107985291 (HGNC:):

LOC107985291 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.27).

BP6

Variant 19-38706105-C-T is Benign according to our data. Variant chr19-38706105-C-T is described in ClinVar as [Benign]. Clinvar id is 259582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38706105-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.54 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN4	NM_004924.6 link	c.546C>T	p.Asn182Asn	synonymous_variant	Exon 5 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.546C>T	p.Asn182Asn	synonymous_variant	Exon 5 of 21	1	NM_004924.6	ENSP00000252699.2		O43707-1

Frequencies

GnomAD3 genomes

AF:

0.392

AC:

59575

AN:

151960

Hom.:

12559

Cov.:

show subpopulations

Gnomad AFR

AF:

0.253

Gnomad AMI

AF:

0.519

Gnomad AMR

AF:

0.347

Gnomad ASJ

AF:

0.408

Gnomad EAS

AF:

0.436

Gnomad SAS

AF:

0.377

Gnomad FIN

AF:

0.499

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.466

Gnomad OTH

AF:

0.374

GnomAD3 exomes

AF:

0.411

AC:

103224

AN:

251394

Hom.:

22179

AF XY:

0.418

AC XY:

56746

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.249

Gnomad AMR exome

AF:

0.282

Gnomad ASJ exome

AF:

0.398

Gnomad EAS exome

AF:

0.431

Gnomad SAS exome

AF:

0.392

Gnomad FIN exome

AF:

0.480

Gnomad NFE exome

AF:

0.463

Gnomad OTH exome

AF:

0.399

GnomAD4 exome

AF:

0.458

AC:

669353

AN:

1461412

Hom.:

156539

Cov.:

AF XY:

0.456

AC XY:

331326

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.238

Gnomad4 AMR exome

AF:

0.286

Gnomad4 ASJ exome

AF:

0.395

Gnomad4 EAS exome

AF:

0.521

Gnomad4 SAS exome

AF:

0.397

Gnomad4 FIN exome

AF:

0.479

Gnomad4 NFE exome

AF:

0.477

Gnomad4 OTH exome

AF:

0.437

GnomAD4 genome

AF:

0.392

AC:

59568

AN:

152078

Hom.:

12552

Cov.:

AF XY:

0.391

AC XY:

29086

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.253

Gnomad4 AMR

AF:

0.346

Gnomad4 ASJ

AF:

0.408

Gnomad4 EAS

AF:

0.436

Gnomad4 SAS

AF:

0.377

Gnomad4 FIN

AF:

0.499

Gnomad4 NFE

AF:

0.466

Gnomad4 OTH

AF:

0.370

Alfa

AF:

0.442

Hom.:

12747

Bravo

AF:

0.372

Asia WGS

AF:

0.341

AC:

1188

AN:

3476

EpiCase

AF:

0.437

EpiControl

AF:

0.442

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Focal segmental glomerulosclerosis 1

Benign:4

Apr 12, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 46% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 43. Only high quality variants are reported. -

not provided

Benign:3

Jul 05, 2018

GeneDx

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

0.71

DANN

Benign

0.67

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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