19-38647800-G-T

Position:

chr19-38647800-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BS1_SupportingBS2

The NM_004924.6(ACTN4):c.55G>T(p.Gly19Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000553 in 1,555,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

ACTN4
NM_004924.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.90

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:

ACTN4 (HGNC:):

ACTN4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTN4. . Gene score misZ 4.1552 (greater than the threshold 3.09). Trascript score misZ 5.6825 (greater than threshold 3.09). GenCC has associacion of gene with familial idiopathic steroid-resistant nephrotic syndrome, focal segmental glomerulosclerosis 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.39076665).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000526 (8/152178) while in subpopulation NFE AF= 0.000118 (8/68018). AF 95% confidence interval is 0.0000584. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTN4	NM_004924.6 linkuse as main transcript	c.55G>T	p.Gly19Cys	missense_variant	1/21	ENST00000252699.7	NP_004915.2	O43707-1A0A0S2Z3G9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7 linkuse as main transcript	c.55G>T	p.Gly19Cys	missense_variant	1/21	1	NM_004924.6	ENSP00000252699.2		O43707-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000123

AC:

AN:

162204

Hom.:

AF XY:

0.00

AC XY:

AN XY:

88572

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000957

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000148

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000556

AC:

AN:

1403232

Hom.:

Cov.:

AF XY:

0.0000504

AC XY:

AN XY:

694250

show subpopulations

Gnomad4 AFR exome

AF:

0.0000330

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:

0.0000682

Gnomad4 OTH exome

AF:

0.0000517

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000566

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.00000856

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2021

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals with ACTN4-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces glycine with cysteine at codon 19 of the ACTN4 protein (p.Gly19Cys). The glycine residue is moderately conserved and there is a large physicochemical difference between glycine and cysteine. -

Focal segmental glomerulosclerosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Jan 05, 2024

This sequence change in ACTN4 is predicted to replace glycine with cysteine at codon 19, p.(Gly19Cys). The glycine residue is moderately conserved (100 vertebrates, Multiz Alignments), and is located in the Actin-binding domain. There is a large physicochemical difference between glycine and cysteine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.007% (82/1,152,342 alleles) in the European (non-Finnish) population. To our knowledge, this variant has not been previously reported in the relevant scientific literature and has been reported as a variant of uncertain significance in ClinVar (ID: 1434698). Computational evidence is uninformative for the missense substitution (REVEL = 0.323). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: none. -

Focal segmental glomerulosclerosis 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;.;T

Eigen

Benign

-0.037

Eigen_PC

Benign

-0.052

FATHMM_MKL

Uncertain

0.95

M_CAP

Pathogenic

0.85

MetaRNN

Benign

0.39

T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.0

N;N;.

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.60

N;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.053

T;D;D

Sift4G

Benign

0.11

T;D;D

Polyphen

1.0

D;.;.

Vest4

0.32

MVP

0.91

MPC

1.4

ClinPred

0.22

GERP RS

2.6

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.9

Varity_R

0.14

gMVP

0.54

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