Variant 19-38647906-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_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

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a region_of_interest Actin-binding (size 268) in uniprot entity ACTN4_HUMAN there are 17 pathogenic changes around while only 4 benign (81%) in NM_004924.6

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, ACTN4

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN4	NM_004924.6 linkuse as main transcript	c.161A>G	p.Lys54Arg	missense_variant, splice_region_variant	1/21	ENST00000252699.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN4	ENST00000252699.7 linkuse as main transcript	c.161A>G	p.Lys54Arg	missense_variant, splice_region_variant	1/21	1	NM_004924.6	A1	O43707-1

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Corticosteroids response

Other:1

drug response, no assertion criteria provided

research

Genetic Testing Lab, Ashok and Rita Patel Institute of Integrated Study and Research in Biotechnology and Allied Sciences

May 20, 2022

Depending upon patients response to standard corticosteroids therapy, they were classified to be either Steroid resistance(SRNS)(poor metabolizer) or steroid sensitive(SSNS)(likley responsive) likley responsive

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;.;D

Eigen

Benign

0.088

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.96

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.41

T;T;T

MetaSVM

Uncertain

0.71

MutationAssessor

Benign

1.8

L;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-2.3

N;N;N

REVEL

Uncertain

0.61

Sift

Uncertain

0.0030

D;D;D

Sift4G

Benign

0.073

T;D;D

Polyphen

0.0010

B;.;.

Vest4

0.32

MutPred

0.71

Loss of methylation at K54 (P = 0.0071);Loss of methylation at K54 (P = 0.0071);Loss of methylation at K54 (P = 0.0071);

MVP

0.96

MPC

1.1

ClinPred

0.88

GERP RS

4.8

Varity_R

0.43

gMVP

0.74

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over