chr19-38697472-G-A

Variant names:

• chr19-38697472-G-A
• rs11083475
• NM_004924.6:c.163-3128G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004924.6(ACTN4):​c.163-3128G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 152,244 control chromosomes in the GnomAD database, including 12,548 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.39 (12548 hom., cov: 35)
• Consequence: ACTN4 NM_004924.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.190
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• focal segmental glomerulosclerosis 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.469 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN4	NM_004924.6	c.163-3128G>A		intron_variant	Intron 1 of 20	ENST00000252699.7	NP_004915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7	c.163-3128G>A		intron_variant	Intron 1 of 20	1	NM_004924.6	ENSP00000252699.2

Frequencies

GnomAD3 genomes AF: 0.388 AC: 59062 AN: 152126 Hom.: 12556 Cov.: 35

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.519

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.437

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.371

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.388 AC: 59050 AN: 152244 Hom.: 12548 Cov.: 35 AF XY: 0.387 AC XY: 28828 AN XY: 74430

African (AFR) AF: 0.224 AC: 9320 AN: 41558

American (AMR) AF: 0.352 AC: 5391 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 1420 AN: 3470

East Asian (EAS) AF: 0.437 AC: 2259 AN: 5172

South Asian (SAS) AF: 0.378 AC: 1826 AN: 4832

European-Finnish (FIN) AF: 0.500 AC: 5305 AN: 10602

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.474 AC: 32220 AN: 68002

Other (OTH) AF: 0.367 AC: 774 AN: 2108

Alfa AF: 0.414 Hom.: 13225

Bravo AF: 0.367

Asia WGS AF: 0.338 AC: 1177 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	14
DANN	Benign	0.67
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11083475; hg19: chr19-39188112;