Genetic Variant ACTN4:p.Lys54Arg (chr19-38647906-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_004924.6(ACTN4):c.161A>G(p.Lys54Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as drug response (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ACTN4
NM_004924.6 missense, splice_region

Scores

Splicing: ADA: 0.9998

Clinical Significance

drug response no assertion criteria provided O:1

Conservation

PhyloP100: 5.74

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.161A>G	p.Lys54Arg	missense splice_region	Exon 1 of 21	NP_004915.2
ACTN4	NM_001440296.1		c.161A>G	p.Lys54Arg	missense splice_region	Exon 1 of 22	NP_001427225.1
ACTN4	NM_001440300.1		c.161A>G	p.Lys54Arg	missense splice_region	Exon 1 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.161A>G	p.Lys54Arg	missense splice_region	Exon 1 of 21	ENSP00000252699.2	O43707-1
ACTN4	ENST00000424234.7	TSL:1	c.161A>G	p.Lys54Arg	missense splice_region	Exon 1 of 21	ENSP00000411187.4	F5GXS2
ACTN4	ENST00000390009.7	TSL:1	c.161A>G	p.Lys54Arg	missense splice_region	Exon 1 of 14	ENSP00000439497.1	O43707-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1218644

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

598252

African (AFR)

AF:

0.00

AC:

AN:

23002

American (AMR)

AF:

0.00

AC:

AN:

25490

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17212

East Asian (EAS)

AF:

0.00

AC:

AN:

22352

South Asian (SAS)

AF:

0.00

AC:

AN:

71888

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3496

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

972012

Other (OTH)

AF:

0.00

AC:

AN:

45922

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:drug response

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Corticosteroids response (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

Eigen

Benign

0.088

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.96

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.41

MetaSVM

Uncertain

0.71

MutationAssessor

Benign

1.8

PhyloP100

5.7

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.61

Sift

Uncertain

0.0030

Sift4G

Benign

0.073

Polyphen

0.0010

Vest4

0.32

MutPred

0.71

Loss of methylation at K54 (P = 0.0071)

MVP

0.96

MPC

1.1

ClinPred

0.88

GERP RS

4.8

PromoterAI

-0.056

Neutral

(source)

Varity_R

0.43

gMVP

0.74

Mutation Taster

=24/76

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.96

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over