rs2368475

Positions:

• chr19-38705095-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004924.6(ACTN4):​c.484+75C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 1,358,192 control chromosomes in the GnomAD database, including 906 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (85 hom., cov: 33)
  • Exomes 𝑓: 0.028 (821 hom.)
• Consequence: ACTN4 NM_004924.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0280

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-38705095-C-T is Benign according to our data. Variant chr19-38705095-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1191708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.058 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTN4	NM_004924.6	c.484+75C>T		intron_variant		ENST00000252699.7	NP_004915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7	c.484+75C>T		intron_variant		1	NM_004924.6	ENSP00000252699.2

Frequencies

GnomAD3 genomes AF: 0.0256 AC: 3892 AN: 152190 Hom.: 84 Cov.: 33

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0609

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0315

Gnomad FIN AF: 0.0383

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0237

Gnomad OTH AF: 0.0282

GnomAD4 exome AF: 0.0277 AC: 33406 AN: 1205884 Hom.: 821 AF XY: 0.0277 AC XY: 16930 AN XY: 611696

Gnomad4 AFR exome AF: 0.0176

Gnomad4 AMR exome AF: 0.123

Gnomad4 ASJ exome AF: 0.0244

Gnomad4 EAS exome AF: 0.000130

Gnomad4 SAS exome AF: 0.0346

Gnomad4 FIN exome AF: 0.0497

Gnomad4 NFE exome AF: 0.0228

Gnomad4 OTH exome AF: 0.0255

GnomAD4 genome AF: 0.0257 AC: 3911 AN: 152308 Hom.: 85 Cov.: 33 AF XY: 0.0268 AC XY: 1995 AN XY: 74468

Gnomad4 AFR AF: 0.0157

Gnomad4 AMR AF: 0.0613

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0323

Gnomad4 FIN AF: 0.0383

Gnomad4 NFE AF: 0.0237

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0268 Hom.: 9

Bravo AF: 0.0288

Asia WGS AF: 0.0160 AC: 54 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.42
DANN	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2368475; hg19: chr19-39195735;