rs3745859

Variant names:

• chr19-38706105-C-T
• rs3745859
• NM_004924.6:c.546C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004924.6(ACTN4):​c.546C>T​(p.Asn182Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,613,490 control chromosomes in the GnomAD database, including 169,091 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12552 hom., cov: 32)
  • Exomes 𝑓: 0.46 (156539 hom.)
• Consequence: ACTN4 NM_004924.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.54
• Publications: 30 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000298338 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 19-38706105-C-T is Benign according to our data. Variant chr19-38706105-C-T is described in ClinVar as Benign. ClinVar VariationId is 259582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.54 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004924.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	NM_004924.6	MANE Select	c.546C>T	p.Asn182Asn	synonymous	Exon 5 of 21	NP_004915.2
	ACTN4	NM_001440296.1		c.546C>T	p.Asn182Asn	synonymous	Exon 5 of 22	NP_001427225.1
	ACTN4	NM_001440300.1		c.546C>T	p.Asn182Asn	synonymous	Exon 5 of 22	NP_001427229.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	ENST00000252699.7	TSL:1 MANE Select	c.546C>T	p.Asn182Asn	synonymous	Exon 5 of 21	ENSP00000252699.2	O43707-1
	ACTN4	ENST00000424234.7	TSL:1	c.546C>T	p.Asn182Asn	synonymous	Exon 5 of 21	ENSP00000411187.4	F5GXS2
	ACTN4	ENST00000390009.7	TSL:1	c.163-8364C>T		intron	N/A	ENSP00000439497.1	O43707-2

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59575 AN: 151960 Hom.: 12559 Cov.: 32

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.519

Gnomad AMR AF: 0.347

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.436

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.499

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.374

GnomAD2 exomes AF: 0.411 AC: 103224 AN: 251394 AF XY: 0.418

Gnomad AFR exome AF: 0.249

Gnomad AMR exome AF: 0.282

Gnomad ASJ exome AF: 0.398

Gnomad EAS exome AF: 0.431

Gnomad FIN exome AF: 0.480

Gnomad NFE exome AF: 0.463

Gnomad OTH exome AF: 0.399

GnomAD4 exome AF: 0.458 AC: 669353 AN: 1461412 Hom.: 156539 Cov.: 48 AF XY: 0.456 AC XY: 331326 AN XY: 727058

African (AFR) AF: 0.238 AC: 7973 AN: 33472

American (AMR) AF: 0.286 AC: 12781 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 10327 AN: 26130

East Asian (EAS) AF: 0.521 AC: 20671 AN: 39692

South Asian (SAS) AF: 0.397 AC: 34247 AN: 86252

European-Finnish (FIN) AF: 0.479 AC: 25569 AN: 53404

Middle Eastern (MID) AF: 0.286 AC: 1647 AN: 5766

European-Non Finnish (NFE) AF: 0.477 AC: 529735 AN: 1111610

Other (OTH) AF: 0.437 AC: 26403 AN: 60376

GnomAD4 genome AF: 0.392 AC: 59568 AN: 152078 Hom.: 12552 Cov.: 32 AF XY: 0.391 AC XY: 29086 AN XY: 74338

African (AFR) AF: 0.253 AC: 10494 AN: 41478

American (AMR) AF: 0.346 AC: 5293 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 1414 AN: 3468

East Asian (EAS) AF: 0.436 AC: 2250 AN: 5160

South Asian (SAS) AF: 0.377 AC: 1821 AN: 4826

European-Finnish (FIN) AF: 0.499 AC: 5282 AN: 10584

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

European-Non Finnish (NFE) AF: 0.466 AC: 31698 AN: 67962

Other (OTH) AF: 0.370 AC: 780 AN: 2110

Alfa AF: 0.437 Hom.: 14198

Bravo AF: 0.372

Asia WGS AF: 0.341 AC: 1188 AN: 3476

EpiCase AF: 0.437

EpiControl AF: 0.442

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Focal segmental glomerulosclerosis 1 (4)
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	0.71
DANN	Benign	0.67
PhyloP100		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs3745859; hg19: chr19-39196745; COSMIC: COSV53151301; COSMIC: COSV53151301;