rs113969422

chr19-38729366-C-Achr19-38729366-C-Gchr19-38729366-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004924.6(ACTN4):c.2670C>A(p.Asp890Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,612,686 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D890D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (22 hom.)
• Consequence: ACTN4 NM_004924.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.03

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ACTN4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0074783266).
• BP6: Variant 19-38729366-C-A is Benign according to our data. Variant chr19-38729366-C-A is described in ClinVar as [Benign]. Clinvar id is 259577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0035 (532/152090) while in subpopulation AFR AF= 0.00933 (387/41494). AF 95% confidence interval is 0.00856. There are 5 homozygotes in gnomad4. There are 254 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 532 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN4	NM_004924.6	c.2670C>A	p.Asp890Glu	missense_variant	21/21	ENST00000252699.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN4	ENST00000252699.7	c.2670C>A	p.Asp890Glu	missense_variant	21/21	1	NM_004924.6	A1

Frequencies

GnomAD3 genomes AF: 0.00350 AC: 532 AN: 151972 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00935

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.0286

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00224 AC: 558 AN: 249208 Hom.: 7 AF XY: 0.00194 AC XY: 263 AN XY: 135436

Gnomad AFR exome AF: 0.00956

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.0325

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000392

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.00111 AC: 1619 AN: 1460596 Hom.: 22 Cov.: 36 AF XY: 0.00104 AC XY: 754 AN XY: 726620

Gnomad4 AFR exome AF: 0.0105

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.0330

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000160

Gnomad4 OTH exome AF: 0.00285

GnomAD4 genome AF: 0.00350 AC: 532 AN: 152090 Hom.: 5 Cov.: 31 AF XY: 0.00342 AC XY: 254 AN XY: 74364

Gnomad4 AFR AF: 0.00933

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.0286

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00182 Hom.: 0

Bravo AF: 0.00380

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00189 AC: 229

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Focal segmental glomerulosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 18, 2020

- -

Focal segmental glomerulosclerosis 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	0.062
Dann	Benign	0.57
DEOGEN2	Benign	0.40	T;.;T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.26	N
MetaRNN	Benign	0.0075	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.1	M;.;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.19	T;T;T;T
Sift4G	Benign	0.48	T;T;T;T
Polyphen		0.0010	B;.;.;.
Vest4		0.49
MutPred		0.42		Loss of relative solvent accessibility (P = 0.107);.;.;.;
MVP		0.69
MPC		1.7
ClinPred		0.029	T
GERP RS		-7.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.12
gMVP		0.43

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

Other links and lift over

dbSNP: rs113969422; hg19: chr19-39220006;