rs11553600

chr19-38706096-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004924.6(ACTN4):c.537G>A(p.Pro179=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,613,962 control chromosomes in the GnomAD database, including 24,878 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2028 hom., cov: 33)
  • Exomes 𝑓: 0.17 (22850 hom.)
• Consequence: ACTN4 NM_004924.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.55

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]

LOC107985291 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 19-38706096-G-A is Benign according to our data. Variant chr19-38706096-G-A is described in ClinVar as [Benign]. Clinvar id is 259581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38706096-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.55 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN4	NM_004924.6	c.537G>A	p.Pro179=	synonymous_variant	5/21	ENST00000252699.7
LOC107985291	XR_001753937.2	n.170-3932C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN4	ENST00000252699.7	c.537G>A	p.Pro179=	synonymous_variant	5/21	1	NM_004924.6	A1

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22844 AN: 152118 Hom.: 2028 Cov.: 33

Gnomad AFR AF: 0.0807

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.00810

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.181

GnomAD3 exomes AF: 0.157 AC: 39589 AN: 251456 Hom.: 3662 AF XY: 0.163 AC XY: 22160 AN XY: 135910

Gnomad AFR exome AF: 0.0788

Gnomad AMR exome AF: 0.105

Gnomad ASJ exome AF: 0.218

Gnomad EAS exome AF: 0.00386

Gnomad SAS exome AF: 0.161

Gnomad FIN exome AF: 0.166

Gnomad NFE exome AF: 0.199

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.172 AC: 251223 AN: 1461726 Hom.: 22850 Cov.: 32 AF XY: 0.173 AC XY: 126018 AN XY: 727186

Gnomad4 AFR exome AF: 0.0811

Gnomad4 AMR exome AF: 0.111

Gnomad4 ASJ exome AF: 0.218

Gnomad4 EAS exome AF: 0.00229

Gnomad4 SAS exome AF: 0.163

Gnomad4 FIN exome AF: 0.164

Gnomad4 NFE exome AF: 0.183

Gnomad4 OTH exome AF: 0.168

GnomAD4 genome AF: 0.150 AC: 22853 AN: 152236 Hom.: 2028 Cov.: 33 AF XY: 0.149 AC XY: 11068 AN XY: 74438

Gnomad4 AFR AF: 0.0808

Gnomad4 AMR AF: 0.157

Gnomad4 ASJ AF: 0.218

Gnomad4 EAS AF: 0.00812

Gnomad4 SAS AF: 0.158

Gnomad4 FIN AF: 0.159

Gnomad4 NFE AF: 0.192

Gnomad4 OTH AF: 0.180

Alfa AF: 0.177 Hom.: 1857

Bravo AF: 0.146

Asia WGS AF: 0.0830 AC: 288 AN: 3476

EpiCase AF: 0.213

EpiControl AF: 0.210

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	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

Focal segmental glomerulosclerosis 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	0.56
Dann	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs11553600; hg19: chr19-39196736; COSMIC: COSV53145434; COSMIC: COSV53145434;