chr19-38723993-C-T

Position:

chr19-38723993-C-T

Variant summary

Our verdict is Benign. Variant got -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

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 385 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTN4	NM_004924.6 link	c.1608C>T	p.Arg536Arg	synonymous_variant	14/21	ENST00000252699.7	NP_004915.2	O43707-1A0A0S2Z3G9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7 link	c.1608C>T	p.Arg536Arg	synonymous_variant	14/21	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

GnomAD3 exomes

AF:

0.00359

AC:

902

AN:

251208

Hom.:

AF XY:

0.00383

AC XY:

521

AN XY:

135866

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 SAS exome

AF:

0.00536

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

Gnomad4 AFR exome

AF:

0.000896

Gnomad4 AMR exome

AF:

0.00342

Gnomad4 ASJ exome

AF:

0.0175

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00519

Gnomad4 FIN exome

AF:

0.0000941

Gnomad4 NFE exome

AF:

0.00250

Gnomad4 OTH exome

AF:

0.00558

GnomAD4 genome

AF:

0.00253

AC:

385

AN:

152220

Hom.:

Cov.:

AF XY:

0.00267

AC XY:

199

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.000458

Gnomad4 AMR

AF:

0.00360

Gnomad4 ASJ

AF:

0.0156

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00352

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00312

Gnomad4 OTH

AF:

0.00568

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	ACTN4: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 13, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	May 06, 2022	- -

Focal segmental glomerulosclerosis 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 03, 2021	- -

Focal segmental glomerulosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 23, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.53

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