rs2306197

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000588618.5(ACTN4):n.1611C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,591,890 control chromosomes in the GnomAD database, including 1,459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 135 hom., cov: 33)

Exomes 𝑓: 0.015 ( 1324 hom. )

Consequence

ACTN4
ENST00000588618.5 non_coding_transcript_exon

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -3.82

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

focal segmental glomerulosclerosis 1
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACTN4 links:

ENSG00000298338 (HGNC:):

ENSG00000298338 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 19-38721760-C-T is Benign according to our data. Variant chr19-38721760-C-T is described in ClinVar as Benign. ClinVar VariationId is 1248068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN4	NM_004924.6 link	c.1442+72C>T		intron_variant	Intron 12 of 20	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.1442+72C>T		intron_variant	Intron 12 of 20	1	NM_004924.6	ENSP00000252699.2		O43707-1

Frequencies

GnomAD3 genomes

AF:

0.0202

AC:

3072

AN:

152232

Hom.:

132

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0275

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00955

Gnomad ASJ

AF:

0.00806

Gnomad EAS

AF:

0.131

Gnomad SAS

AF:

0.150

Gnomad FIN

AF:

0.0121

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00256

Gnomad OTH

AF:

0.0210

GnomAD2 exomes

AF:

0.0344

AC:

7602

AN:

221140

AF XY:

0.0391

show subpopulations

Gnomad AFR exome

AF:

0.0302

Gnomad AMR exome

AF:

0.00433

Gnomad ASJ exome

AF:

0.0102

Gnomad EAS exome

AF:

0.137

Gnomad FIN exome

AF:

0.0123

Gnomad NFE exome

AF:

0.00241

Gnomad OTH exome

AF:

0.0229

GnomAD4 exome

AF:

0.0148

AC:

21371

AN:

1439540

Hom.:

1324

Cov.:

AF XY:

0.0184

AC XY:

13151

AN XY:

716240

show subpopulations

African (AFR)

AF:

0.0314

AC:

1040

AN:

33108

American (AMR)

AF:

0.00405

AC:

177

AN:

43754

Ashkenazi Jewish (ASJ)

AF:

0.00956

AC:

248

AN:

25952

East Asian (EAS)

AF:

0.114

AC:

4435

AN:

39012

South Asian (SAS)

AF:

0.133

AC:

11334

AN:

85128

European-Finnish (FIN)

AF:

0.0126

AC:

509

AN:

40302

Middle Eastern (MID)

AF:

0.0217

AC:

125

AN:

5754

European-Non Finnish (NFE)

AF:

0.00182

AC:

2019

AN:

1106594

Other (OTH)

AF:

0.0248

AC:

1484

AN:

59936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

1080

2160

3240

4320

5400

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

296

592

888

1184

1480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0203

AC:

3086

AN:

152350

Hom.:

135

Cov.:

AF XY:

0.0234

AC XY:

1740

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0275

AC:

1145

AN:

41574

American (AMR)

AF:

0.00954

AC:

146

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00806

AC:

AN:

3472

East Asian (EAS)

AF:

0.132

AC:

683

AN:

5186

South Asian (SAS)

AF:

0.150

AC:

722

AN:

4826

European-Finnish (FIN)

AF:

0.0121

AC:

129

AN:

10628

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00256

AC:

174

AN:

68032

Other (OTH)

AF:

0.0269

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

156

313

469

626

782

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0115

Hom.:

Bravo

AF:

0.0174

Asia WGS

AF:

0.189

AC:

653

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 10, 2018

GeneDx

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

- -

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

-0.91

CADD

Benign

0.88

(source)

DANN

Benign

0.63

PhyloP100

-3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over