rs1105759

Variant names:

• chr19-38726867-G-A
• rs1105759
• NM_004924.6:c.2191-90G>A

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.2191-90G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0658 in 1,569,730 control chromosomes in the GnomAD database, including 3,710 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (295 hom., cov: 32)
  • Exomes 𝑓: 0.066 (3415 hom.)
• Consequence: ACTN4 NM_004924.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.18
• 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=-0.9).
• BP6: Variant 19-38726867-G-A is Benign according to our data. Variant chr19-38726867-G-A is described in ClinVar as Benign. ClinVar VariationId is 1276880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN4	NM_004924.6	c.2191-90G>A		intron_variant	Intron 17 of 20	ENST00000252699.7	NP_004915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7	c.2191-90G>A		intron_variant	Intron 17 of 20	1	NM_004924.6	ENSP00000252699.2

Frequencies

GnomAD3 genomes AF: 0.0598 AC: 9096 AN: 152098 Hom.: 296 Cov.: 32

Gnomad AFR AF: 0.0595

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0627

Gnomad ASJ AF: 0.0582

Gnomad EAS AF: 0.0457

Gnomad SAS AF: 0.0962

Gnomad FIN AF: 0.0258

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0638

Gnomad OTH AF: 0.0612

GnomAD4 exome AF: 0.0665 AC: 94199 AN: 1417514 Hom.: 3415 AF XY: 0.0675 AC XY: 47395 AN XY: 702372

African (AFR) AF: 0.0618 AC: 1996 AN: 32316

American (AMR) AF: 0.0750 AC: 3051 AN: 40704

Ashkenazi Jewish (ASJ) AF: 0.0634 AC: 1612 AN: 25410

East Asian (EAS) AF: 0.0466 AC: 1743 AN: 37370

South Asian (SAS) AF: 0.102 AC: 8419 AN: 82738

European-Finnish (FIN) AF: 0.0305 AC: 1451 AN: 47552

Middle Eastern (MID) AF: 0.0735 AC: 303 AN: 4124

European-Non Finnish (NFE) AF: 0.0659 AC: 71721 AN: 1088694

Other (OTH) AF: 0.0666 AC: 3903 AN: 58606

GnomAD4 genome AF: 0.0598 AC: 9099 AN: 152216 Hom.: 295 Cov.: 32 AF XY: 0.0588 AC XY: 4377 AN XY: 74418

African (AFR) AF: 0.0594 AC: 2468 AN: 41538

American (AMR) AF: 0.0626 AC: 957 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0582 AC: 202 AN: 3472

East Asian (EAS) AF: 0.0458 AC: 237 AN: 5178

South Asian (SAS) AF: 0.0956 AC: 461 AN: 4820

European-Finnish (FIN) AF: 0.0258 AC: 274 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0639 AC: 4341 AN: 67972

Other (OTH) AF: 0.0620 AC: 131 AN: 2112

Alfa AF: 0.0583 Hom.: 43

Bravo AF: 0.0625

Asia WGS AF: 0.0890 AC: 311 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.68
DANN	Benign	0.54
PhyloP100		-1.2
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: rs1105759; hg19: chr19-39217507;