19-38700607-C-T

Position:

chr19-38700607-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 7P and 4B. PM1PP2PP3_StrongBS2

The NM_004924.6(ACTN4):c.170C>T(p.Thr57Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

ACTN4
NM_004924.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 7.91

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 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

PP2

Missense variant where missense usually causes diseases, ACTN4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.945

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN4	NM_004924.6 linkuse as main transcript	c.170C>T	p.Thr57Met	missense_variant	2/21	ENST00000252699.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN4	ENST00000252699.7 linkuse as main transcript	c.170C>T	p.Thr57Met	missense_variant	2/21	1	NM_004924.6	A1	O43707-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251410

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461414

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727030

show subpopulations

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:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 21, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 981939). This variant has not been reported in the literature in individuals affected with ACTN4-related conditions. This variant is present in population databases (rs768656011, gnomAD 0.007%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 57 of the ACTN4 protein (p.Thr57Met). -

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

Jan 12, 2020

Depending upon response to standard corticosteroid therapy, patients were classified to be either Steroid resistant (SRNS) or steroid sensitive (SSNS). Patients in remission within 4 weeks of corticosteroid therapy were classified as steroid sensitive nephrotic syndrome (SSNS). Patients not in remission within 4 weeks of corticosteroid therapy were classified as Steroid resistant nephrotic syndrome (SRNS). likely responsive

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

H;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-5.1

D;N

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.87

MutPred

0.70

Gain of MoRF binding (P = 0.0864);Gain of MoRF binding (P = 0.0864);

MVP

0.97

MPC

2.6

ClinPred

1.0

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.76

gMVP

0.94

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