rs12981131

Variant names:

• chr19-38728054-A-G
• rs12981131
• NM_004924.6:c.2418+28A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-38728054-A-G
• chr19-38728054-A-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.2418+28A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.066 in 1,589,288 control chromosomes in the GnomAD database, including 3,783 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (317 hom., cov: 31)
  • Exomes 𝑓: 0.066 (3466 hom.)
• Consequence: ACTN4 NM_004924.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.499
• Publications: 4 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=-0.86).
• BP6: Variant 19-38728054-A-G is Benign according to our data. Variant chr19-38728054-A-G is described in ClinVar as Benign. ClinVar VariationId is 1250001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0892 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.2418+28A>G		intron	N/A	NP_004915.2
	ACTN4	NM_001440296.1		c.2418+28A>G		intron	N/A	NP_001427225.1
	ACTN4	NM_001440300.1		c.2418+28A>G		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.2418+28A>G		intron	N/A	ENSP00000252699.2
	ACTN4	ENST00000424234.7	TSL:1	c.2418+28A>G		intron	N/A	ENSP00000411187.4
	ACTN4	ENST00000390009.7	TSL:1	c.1761+28A>G		intron	N/A	ENSP00000439497.1

Frequencies

GnomAD3 genomes AF: 0.0633 AC: 9589 AN: 151470 Hom.: 318 Cov.: 31

Gnomad AFR AF: 0.0717

Gnomad AMI AF: 0.00662

Gnomad AMR AF: 0.0637

Gnomad ASJ AF: 0.0584

Gnomad EAS AF: 0.0464

Gnomad SAS AF: 0.0970

Gnomad FIN AF: 0.0258

Gnomad MID AF: 0.0769

Gnomad NFE AF: 0.0639

Gnomad OTH AF: 0.0599

GnomAD2 exomes AF: 0.0658 AC: 13730 AN: 208672 AF XY: 0.0671

Gnomad AFR exome AF: 0.0722

Gnomad AMR exome AF: 0.0705

Gnomad ASJ exome AF: 0.0617

Gnomad EAS exome AF: 0.0395

Gnomad FIN exome AF: 0.0283

Gnomad NFE exome AF: 0.0639

Gnomad OTH exome AF: 0.0702

GnomAD4 exome AF: 0.0663 AC: 95290 AN: 1437700 Hom.: 3466 Cov.: 31 AF XY: 0.0672 AC XY: 47922 AN XY: 713388

African (AFR) AF: 0.0700 AC: 2296 AN: 32784

American (AMR) AF: 0.0730 AC: 3035 AN: 41576

Ashkenazi Jewish (ASJ) AF: 0.0632 AC: 1626 AN: 25746

East Asian (EAS) AF: 0.0456 AC: 1743 AN: 38262

South Asian (SAS) AF: 0.101 AC: 8406 AN: 83000

European-Finnish (FIN) AF: 0.0305 AC: 1553 AN: 50874

Middle Eastern (MID) AF: 0.0696 AC: 400 AN: 5744

European-Non Finnish (NFE) AF: 0.0657 AC: 72255 AN: 1100200

Other (OTH) AF: 0.0668 AC: 3976 AN: 59514

GnomAD4 genome AF: 0.0633 AC: 9589 AN: 151588 Hom.: 317 Cov.: 31 AF XY: 0.0622 AC XY: 4605 AN XY: 74066

African (AFR) AF: 0.0715 AC: 2957 AN: 41338

American (AMR) AF: 0.0636 AC: 969 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.0584 AC: 202 AN: 3458

East Asian (EAS) AF: 0.0465 AC: 236 AN: 5076

South Asian (SAS) AF: 0.0964 AC: 462 AN: 4792

European-Finnish (FIN) AF: 0.0258 AC: 273 AN: 10572

Middle Eastern (MID) AF: 0.0759 AC: 22 AN: 290

European-Non Finnish (NFE) AF: 0.0639 AC: 4334 AN: 67810

Other (OTH) AF: 0.0607 AC: 128 AN: 2108

Alfa AF: 0.0380 Hom.: 27

Bravo AF: 0.0664

Asia WGS AF: 0.0910 AC: 315 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: 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	-0.86
CADD	Benign	1.9
DANN	Benign	0.46
PhyloP100		-0.50
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)		0.0		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: rs12981131; hg19: chr19-39218694;