rs2368475

Variant names:

• chr19-38705095-C-T
• rs2368475
• NM_004924.6:c.484+75C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 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

ENSG00000298338 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	NM_004924.6	MANE Select	c.484+75C>T		intron	N/A	NP_004915.2
	ACTN4	NM_001440296.1		c.484+75C>T		intron	N/A	NP_001427225.1
	ACTN4	NM_001440300.1		c.484+75C>T		intron	N/A	NP_001427229.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	ENST00000252699.7	TSL:1 MANE Select	c.484+75C>T		intron	N/A	ENSP00000252699.2
	ACTN4	ENST00000424234.7	TSL:1	c.484+75C>T		intron	N/A	ENSP00000411187.4
	ACTN4	ENST00000390009.7	TSL:1	c.163-9374C>T		intron	N/A	ENSP00000439497.1

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

African (AFR) AF: 0.0176 AC: 497 AN: 28192

American (AMR) AF: 0.123 AC: 5334 AN: 43534

Ashkenazi Jewish (ASJ) AF: 0.0244 AC: 598 AN: 24486

East Asian (EAS) AF: 0.000130 AC: 5 AN: 38448

South Asian (SAS) AF: 0.0346 AC: 2788 AN: 80616

European-Finnish (FIN) AF: 0.0497 AC: 2633 AN: 52954

Middle Eastern (MID) AF: 0.0324 AC: 171 AN: 5282

European-Non Finnish (NFE) AF: 0.0228 AC: 20054 AN: 880312

Other (OTH) AF: 0.0255 AC: 1326 AN: 52060

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

African (AFR) AF: 0.0157 AC: 651 AN: 41562

American (AMR) AF: 0.0613 AC: 938 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.0323 AC: 156 AN: 4828

European-Finnish (FIN) AF: 0.0383 AC: 407 AN: 10616

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0237 AC: 1609 AN: 68016

Other (OTH) AF: 0.0279 AC: 59 AN: 2116

Alfa AF: 0.0270 Hom.: 10

Bravo AF: 0.0288

Asia WGS AF: 0.0160 AC: 54 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Focal segmental glomerulosclerosis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.42
DANN	Benign	0.53
PhyloP100		-0.028
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2368475; hg19: chr19-39195735;