dbSNP rs112545413: ACTN4:p.Arg310Gln (chr19-38717102-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004924.6(ACTN4):c.929G>A(p.Arg310Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,613,586 control chromosomes in the GnomAD database, including 236 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R310W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0097 ( 16 hom., cov: 33)

Exomes 𝑓: 0.015 ( 220 hom. )

Consequence

ACTN4
NM_004924.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 3.57

Publications

14 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
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 (MetaRNN=0.00835824).

BP6

Variant 19-38717102-G-A is Benign according to our data. Variant chr19-38717102-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00971 (1479/152350) while in subpopulation SAS AF = 0.0224 (108/4828). AF 95% confidence interval is 0.019. There are 16 homozygotes in GnomAd4. There are 702 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1479 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004924.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ACTN4	NM_004924.6	MANE Select	c.929G>A	p.Arg310Gln	missense	Exon 10 of 21	NP_004915.2
ACTN4	NM_001440296.1		c.929G>A	p.Arg310Gln	missense	Exon 10 of 22	NP_001427225.1
ACTN4	NM_001440300.1		c.929G>A	p.Arg310Gln	missense	Exon 10 of 22	NP_001427229.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACTN4	ENST00000252699.7	TSL:1 MANE Select	c.929G>A	p.Arg310Gln	missense	Exon 10 of 21	ENSP00000252699.2	O43707-1
ACTN4	ENST00000424234.7	TSL:1	c.929G>A	p.Arg310Gln	missense	Exon 10 of 21	ENSP00000411187.4	F5GXS2
ACTN4	ENST00000390009.7	TSL:1	c.272G>A	p.Arg91Gln	missense	Exon 3 of 14	ENSP00000439497.1	O43707-2

Frequencies

GnomAD3 genomes

AF:

0.00972

AC:

1480

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00268

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.00857

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0226

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0151

Gnomad OTH

AF:

0.00766

GnomAD2 exomes

AF:

0.0118

AC:

2927

AN:

248854

AF XY:

0.0131

show subpopulations

Gnomad AFR exome

AF:

0.00213

Gnomad AMR exome

AF:

0.00534

Gnomad ASJ exome

AF:

0.0102

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00248

Gnomad NFE exome

AF:

0.0155

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.0146

AC:

21331

AN:

1461236

Hom.:

220

Cov.:

AF XY:

0.0151

AC XY:

10964

AN XY:

726904

show subpopulations

African (AFR)

AF:

0.00212

AC:

AN:

33474

American (AMR)

AF:

0.00616

AC:

275

AN:

44650

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

300

AN:

26118

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39682

South Asian (SAS)

AF:

0.0241

AC:

2073

AN:

86160

European-Finnish (FIN)

AF:

0.00297

AC:

158

AN:

53216

Middle Eastern (MID)

AF:

0.0168

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0158

AC:

17596

AN:

1111804

Other (OTH)

AF:

0.0126

AC:

759

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

1381

2762

4144

5525

6906

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

662

1324

1986

2648

3310

<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:

0.00971

AC:

1479

AN:

152350

Hom.:

Cov.:

AF XY:

0.00942

AC XY:

702

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.00267

AC:

111

AN:

41580

American (AMR)

AF:

0.00856

AC:

131

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.0224

AC:

108

AN:

4828

European-Finnish (FIN)

AF:

0.00198

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0151

AC:

1028

AN:

68032

Other (OTH)

AF:

0.00758

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

154

230

307

384

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0133

Hom.:

Bravo

AF:

0.00965

TwinsUK

AF:

0.0135

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0130

AC:

112

ExAC

AF:

0.0119

AC:

1446

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.0154

EpiControl

AF:

0.0152

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (4)

Focal segmental glomerulosclerosis 1 (2)

Focal segmental glomerulosclerosis (1)

Intellectual disability, autosomal dominant 14 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

Eigen

Benign

-0.083

Eigen_PC

Benign

0.073

FATHMM_MKL

Uncertain

0.90

MetaRNN

Benign

0.0084

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.5

PhyloP100

3.6

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.2

REVEL

Benign

0.080

Sift

Benign

0.13

Sift4G

Benign

0.28

Polyphen

0.0020

Vest4

0.17

MPC

1.5

ClinPred

0.014

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.21

gMVP

0.73

Mutation Taster

=80/20

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over