19-38676720-A-G

Variant names:

• chr19-38676720-A-G
• rs755690
• NM_004924.6:c.163-23880A>G

Variant summary

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

The NM_004924.6(ACTN4):​c.163-23880A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.523 in 151,932 control chromosomes in the GnomAD database, including 21,186 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 0.52 (21186 hom., cov: 31)
• Consequence: ACTN4 NM_004924.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.848
• Publications: 7 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN4	NM_004924.6	c.163-23880A>G		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.163-23880A>G		intron_variant	Intron 1 of 20	1	NM_004924.6	ENSP00000252699.2

Frequencies

GnomAD3 genomes AF: 0.523 AC: 79450 AN: 151814 Hom.: 21176 Cov.: 31

Gnomad AFR AF: 0.435

Gnomad AMI AF: 0.529

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.494

Gnomad EAS AF: 0.614

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.567

Gnomad MID AF: 0.363

Gnomad NFE AF: 0.563

Gnomad OTH AF: 0.502

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

GnomAD4 genome AF: 0.523 AC: 79494 AN: 151932 Hom.: 21186 Cov.: 31 AF XY: 0.525 AC XY: 38980 AN XY: 74252

African (AFR) AF: 0.435 AC: 18014 AN: 41444

American (AMR) AF: 0.493 AC: 7538 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.494 AC: 1713 AN: 3468

East Asian (EAS) AF: 0.615 AC: 3157 AN: 5134

South Asian (SAS) AF: 0.657 AC: 3161 AN: 4808

European-Finnish (FIN) AF: 0.567 AC: 5991 AN: 10558

Middle Eastern (MID) AF: 0.339 AC: 99 AN: 292

European-Non Finnish (NFE) AF: 0.563 AC: 38277 AN: 67940

Other (OTH) AF: 0.506 AC: 1065 AN: 2106

Alfa AF: 0.556 Hom.: 23158

Bravo AF: 0.511

Asia WGS AF: 0.644 AC: 2239 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.50
DANN	Benign	0.61
PhyloP100		-0.85
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: rs755690; hg19: chr19-39167360;