rs749701

Variant names:

• chr19-38699106-T-C
• rs749701
• NM_004924.6:c.163-1494T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-38699106-T-C
• chr19-38699106-T-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.163-1494T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 152,022 control chromosomes in the GnomAD database, including 20,598 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 0.51 (20598 hom., cov: 33)
• Consequence: ACTN4 NM_004924.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.253
• Publications: 14 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN4	NM_004924.6	c.163-1494T>C		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.163-1494T>C		intron_variant	Intron 1 of 20	1	NM_004924.6	ENSP00000252699.2

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78171 AN: 151904 Hom.: 20583 Cov.: 33

Gnomad AFR AF: 0.404

Gnomad AMI AF: 0.530

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.496

Gnomad EAS AF: 0.614

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.567

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.563

Gnomad OTH AF: 0.500

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

GnomAD4 genome AF: 0.515 AC: 78216 AN: 152022 Hom.: 20598 Cov.: 33 AF XY: 0.516 AC XY: 38372 AN XY: 74306

African (AFR) AF: 0.404 AC: 16724 AN: 41430

American (AMR) AF: 0.491 AC: 7500 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 1720 AN: 3470

East Asian (EAS) AF: 0.614 AC: 3168 AN: 5156

South Asian (SAS) AF: 0.656 AC: 3165 AN: 4822

European-Finnish (FIN) AF: 0.567 AC: 6006 AN: 10586

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.563 AC: 38291 AN: 67962

Other (OTH) AF: 0.502 AC: 1060 AN: 2110

Alfa AF: 0.557 Hom.: 21210

Bravo AF: 0.501

Asia WGS AF: 0.640 AC: 2224 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.4
DANN	Benign	0.65
PhyloP100		-0.25
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: rs749701; hg19: chr19-39189746;