NM_004924.6:c.162+33G>A

Variant names:

• chr19-38647940-G-A
• rs199812484
• NM_004924.6:c.162+33G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004924.6(ACTN4):​c.162+33G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00644 in 1,452,122 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (2 hom., cov: 30)
  • Exomes 𝑓: 0.0066 (37 hom.)
• Consequence: ACTN4 NM_004924.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.184
• Publications: 1 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 19-38647940-G-A is Benign according to our data. Variant chr19-38647940-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1706702.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00472 (717/152014) while in subpopulation SAS AF = 0.0116 (56/4814). AF 95% confidence interval is 0.0092. There are 2 homozygotes in GnomAd4. There are 354 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 717 AD gene.

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.162+33G>A		intron	N/A	NP_004915.2
	ACTN4	NM_001440296.1		c.162+33G>A		intron	N/A	NP_001427225.1
	ACTN4	NM_001440300.1		c.162+33G>A		intron	N/A	NP_001427229.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	ENST00000252699.7	TSL:1 MANE Select	c.162+33G>A		intron	N/A	ENSP00000252699.2	O43707-1
	ACTN4	ENST00000424234.7	TSL:1	c.162+33G>A		intron	N/A	ENSP00000411187.4	F5GXS2
	ACTN4	ENST00000390009.7	TSL:1	c.162+33G>A		intron	N/A	ENSP00000439497.1	O43707-2

Frequencies

GnomAD3 genomes AF: 0.00473 AC: 718 AN: 151896 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.000774

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00703

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00509 AC: 349 AN: 68596 AF XY: 0.00546

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.000989

Gnomad EAS exome AF: 0.000505

Gnomad FIN exome AF: 0.00737

Gnomad NFE exome AF: 0.00553

Gnomad OTH exome AF: 0.00529

GnomAD4 exome AF: 0.00664 AC: 8630 AN: 1300108 Hom.: 37 Cov.: 33 AF XY: 0.00676 AC XY: 4302 AN XY: 636078

African (AFR) AF: 0.00106 AC: 28 AN: 26462

American (AMR) AF: 0.00180 AC: 42 AN: 23276

Ashkenazi Jewish (ASJ) AF: 0.00148 AC: 30 AN: 20320

East Asian (EAS) AF: 0.0000334 AC: 1 AN: 29936

South Asian (SAS) AF: 0.0112 AC: 751 AN: 67280

European-Finnish (FIN) AF: 0.00706 AC: 309 AN: 43746

Middle Eastern (MID) AF: 0.00624 AC: 24 AN: 3848

European-Non Finnish (NFE) AF: 0.00695 AC: 7167 AN: 1031854

Other (OTH) AF: 0.00521 AC: 278 AN: 53386

GnomAD4 genome AF: 0.00472 AC: 717 AN: 152014 Hom.: 2 Cov.: 30 AF XY: 0.00476 AC XY: 354 AN XY: 74308

African (AFR) AF: 0.000772 AC: 32 AN: 41474

American (AMR) AF: 0.00131 AC: 20 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5132

South Asian (SAS) AF: 0.0116 AC: 56 AN: 4814

European-Finnish (FIN) AF: 0.0104 AC: 110 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00704 AC: 478 AN: 67940

Other (OTH) AF: 0.00569 AC: 12 AN: 2108

Alfa AF: 0.00658 Hom.: 6

Asia WGS AF: 0.00404 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely 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	-0.71
CADD	Benign	11
DANN	Benign	0.92
PhyloP100		0.18
PromoterAI		-0.055	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs199812484; hg19: chr19-39138580;