NM_004924.6:c.1998G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_004924.6(ACTN4):c.1998G>A(p.Gln666Gln) variant causes a synonymous change. The variant allele was found at a frequency of 0.00944 in 1,613,652 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0066 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0097 ( 110 hom. )

Consequence

ACTN4
NM_004924.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 6.91

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

BP6

Variant 19-38724553-G-A is Benign according to our data. Variant chr19-38724553-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00658 (1002/152378) while in subpopulation NFE AF= 0.0111 (756/68044). AF 95% confidence interval is 0.0105. There are 8 homozygotes in gnomad4. There are 467 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1002 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN4	NM_004924.6 link	c.1998G>A	p.Gln666Gln	synonymous_variant	Exon 16 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.1998G>A	p.Gln666Gln	synonymous_variant	Exon 16 of 21	1	NM_004924.6	ENSP00000252699.2		O43707-1

Frequencies

GnomAD3 genomes

AF:

0.00659

AC:

1004

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00195

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00911

Gnomad FIN

AF:

0.00668

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0111

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00842

AC:

2106

AN:

250048

Hom.:

AF XY:

0.00872

AC XY:

1182

AN XY:

135510

show subpopulations

Gnomad AFR exome

AF:

0.00204

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.00209

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00882

Gnomad FIN exome

AF:

0.00795

Gnomad NFE exome

AF:

0.0136

Gnomad OTH exome

AF:

0.00588

GnomAD4 exome

AF:

0.00974

AC:

14234

AN:

1461274

Hom.:

110

Cov.:

AF XY:

0.00971

AC XY:

7057

AN XY:

726952

show subpopulations

Gnomad4 AFR exome

AF:

0.00173

Gnomad4 AMR exome

AF:

0.00132

Gnomad4 ASJ exome

AF:

0.00191

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00879

Gnomad4 FIN exome

AF:

0.00847

Gnomad4 NFE exome

AF:

0.0112

Gnomad4 OTH exome

AF:

0.00686

GnomAD4 genome

AF:

0.00658

AC:

1002

AN:

152378

Hom.:

Cov.:

AF XY:

0.00627

AC XY:

467

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.00195

Gnomad4 AMR

AF:

0.00229

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00870

Gnomad4 FIN

AF:

0.00668

Gnomad4 NFE

AF:

0.0111

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00901

Hom.:

Bravo

AF:

0.00584

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00894

EpiControl

AF:

0.00895

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 08, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Focal segmental glomerulosclerosis

Benign:1

Dec 15, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Focal segmental glomerulosclerosis 1

Benign:1

Dec 05, 2021

Genome-Nilou Lab

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

-0.32

CADD

Benign

8.7

DANN

Benign

0.74

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