19-38700683-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004924.6(ACTN4):c.246C>T(p.Leu82=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,614,060 control chromosomes in the GnomAD database, including 1,005 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 85 hom., cov: 32)

Exomes 𝑓: 0.027 ( 920 hom. )

Consequence

ACTN4
NM_004924.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.701

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 19-38700683-C-T is Benign according to our data. Variant chr19-38700683-C-T is described in ClinVar as [Benign]. Clinvar id is 259575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38700683-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.701 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN4	NM_004924.6 linkuse as main transcript	c.246C>T	p.Leu82=	synonymous_variant	2/21	ENST00000252699.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN4	ENST00000252699.7 linkuse as main transcript	c.246C>T	p.Leu82=	synonymous_variant	2/21	1	NM_004924.6	A1	O43707-1

Frequencies

GnomAD3 genomes

AF:

0.0256

AC:

3892

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0157

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0601

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0313

Gnomad FIN

AF:

0.0382

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0238

Gnomad OTH

AF:

0.0283

GnomAD3 exomes

AF:

0.0405

AC:

10182

AN:

251356

Hom.:

491

AF XY:

0.0376

AC XY:

5112

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.0145

Gnomad AMR exome

AF:

0.137

Gnomad ASJ exome

AF:

0.0265

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.0331

Gnomad FIN exome

AF:

0.0489

Gnomad NFE exome

AF:

0.0233

Gnomad OTH exome

AF:

0.0370

GnomAD4 exome

AF:

0.0269

AC:

39300

AN:

1461750

Hom.:

920

Cov.:

AF XY:

0.0269

AC XY:

19587

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.0174

Gnomad4 AMR exome

AF:

0.122

Gnomad4 ASJ exome

AF:

0.0247

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0344

Gnomad4 FIN exome

AF:

0.0498

Gnomad4 NFE exome

AF:

0.0227

Gnomad4 OTH exome

AF:

0.0251

GnomAD4 genome

AF:

0.0257

AC:

3911

AN:

152310

Hom.:

Cov.:

AF XY:

0.0266

AC XY:

1984

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0158

Gnomad4 AMR

AF:

0.0605

Gnomad4 ASJ

AF:

0.0225

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0321

Gnomad4 FIN

AF:

0.0382

Gnomad4 NFE

AF:

0.0238

Gnomad4 OTH

AF:

0.0280

Alfa

AF:

0.0239

Hom.:

Bravo

AF:

0.0288

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.0242

EpiControl

AF:

0.0216

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

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

Aug 20, 2022

- -

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

BayesDel_noAF

Benign

-0.60

Cadd

Benign

7.2

Dann

Benign

0.88

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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