rs12979947

Variant names:

• chr19-38725563-T-C
• rs12979947
• NM_004924.6:c.2011-161T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000252699.7(ACTN4):​c.2011-161T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0571 in 152,264 control chromosomes in the GnomAD database, including 265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.057 (265 hom., cov: 32)
• Consequence: ACTN4 ENST00000252699.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.58
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-38725563-T-C is Benign according to our data. Variant chr19-38725563-T-C is described in ClinVar as Benign. ClinVar VariationId is 1246854.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0889 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000252699.7. 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.2011-161T>C		intron	N/A	NP_004915.2
	ACTN4	NM_001440296.1		c.2011-161T>C		intron	N/A	NP_001427225.1
	ACTN4	NM_001440300.1		c.2011-161T>C		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.2011-161T>C		intron	N/A	ENSP00000252699.2
	ACTN4	ENST00000424234.7	TSL:1	c.2011-161T>C		intron	N/A	ENSP00000411187.4
	ACTN4	ENST00000390009.7	TSL:1	c.1354-161T>C		intron	N/A	ENSP00000439497.1

Frequencies

GnomAD3 genomes AF: 0.0571 AC: 8693 AN: 152146 Hom.: 266 Cov.: 32

Gnomad AFR AF: 0.0503

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0617

Gnomad ASJ AF: 0.0579

Gnomad EAS AF: 0.0462

Gnomad SAS AF: 0.0967

Gnomad FIN AF: 0.0259

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0637

Gnomad OTH AF: 0.0578

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

GnomAD4 genome AF: 0.0571 AC: 8697 AN: 152264 Hom.: 265 Cov.: 32 AF XY: 0.0563 AC XY: 4194 AN XY: 74448

African (AFR) AF: 0.0503 AC: 2088 AN: 41544

American (AMR) AF: 0.0616 AC: 942 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0579 AC: 201 AN: 3472

East Asian (EAS) AF: 0.0463 AC: 240 AN: 5182

South Asian (SAS) AF: 0.0961 AC: 464 AN: 4826

European-Finnish (FIN) AF: 0.0259 AC: 275 AN: 10620

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0638 AC: 4335 AN: 67998

Other (OTH) AF: 0.0586 AC: 124 AN: 2116

Alfa AF: 0.0533 Hom.: 18

Bravo AF: 0.0594

Asia WGS AF: 0.0890 AC: 311 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.095
DANN	Benign	0.53
PhyloP100		-2.6
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: rs12979947; hg19: chr19-39216203;