rs12974733

Variant names:

• chr19-38728920-G-T
• rs12974733
• NM_004924.6:c.2419-76G>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.2419-76G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0649 in 1,579,668 control chromosomes in the GnomAD database, including 3,677 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (264 hom., cov: 31)
  • Exomes 𝑓: 0.066 (3413 hom.)
• Consequence: ACTN4 NM_004924.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0660
• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-38728920-G-T is Benign according to our data. Variant chr19-38728920-G-T is described in ClinVar as [Benign]. Clinvar id is 1246606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0882 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN4	NM_004924.6	c.2419-76G>T		intron_variant	Intron 19 of 20	ENST00000252699.7	NP_004915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7	c.2419-76G>T		intron_variant	Intron 19 of 20	1	NM_004924.6	ENSP00000252699.2

Frequencies

GnomAD3 genomes AF: 0.0570 AC: 8677 AN: 152130 Hom.: 265 Cov.: 31

Gnomad AFR AF: 0.0501

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0614

Gnomad ASJ AF: 0.0579

Gnomad EAS AF: 0.0457

Gnomad SAS AF: 0.0959

Gnomad FIN AF: 0.0259

Gnomad MID AF: 0.0701

Gnomad NFE AF: 0.0638

Gnomad OTH AF: 0.0580

GnomAD4 exome AF: 0.0657 AC: 93851 AN: 1427420 Hom.: 3413 AF XY: 0.0667 AC XY: 47501 AN XY: 711902

African (AFR) AF: 0.0515 AC: 1685 AN: 32750

American (AMR) AF: 0.0729 AC: 3250 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.0633 AC: 1640 AN: 25924

East Asian (EAS) AF: 0.0457 AC: 1805 AN: 39526

South Asian (SAS) AF: 0.101 AC: 8648 AN: 85306

European-Finnish (FIN) AF: 0.0304 AC: 1573 AN: 51712

Middle Eastern (MID) AF: 0.0734 AC: 303 AN: 4126

European-Non Finnish (NFE) AF: 0.0655 AC: 71056 AN: 1084408

Other (OTH) AF: 0.0659 AC: 3891 AN: 59076

GnomAD4 genome AF: 0.0570 AC: 8681 AN: 152248 Hom.: 264 Cov.: 31 AF XY: 0.0562 AC XY: 4181 AN XY: 74432

African (AFR) AF: 0.0501 AC: 2080 AN: 41554

American (AMR) AF: 0.0613 AC: 938 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0579 AC: 201 AN: 3470

East Asian (EAS) AF: 0.0458 AC: 236 AN: 5154

South Asian (SAS) AF: 0.0954 AC: 460 AN: 4824

European-Finnish (FIN) AF: 0.0259 AC: 275 AN: 10628

Middle Eastern (MID) AF: 0.0685 AC: 20 AN: 292

European-Non Finnish (NFE) AF: 0.0638 AC: 4341 AN: 68000

Other (OTH) AF: 0.0588 AC: 124 AN: 2110

Alfa AF: 0.0537 Hom.: 18

Bravo AF: 0.0595

Asia WGS AF: 0.0900 AC: 313 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	-0.84
CADD	Benign	0.39
DANN	Benign	0.85
PhyloP100		0.066
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs12974733; hg19: chr19-39219560; COSMIC: COSV53144365; COSMIC: COSV53144365;