19-38724693-C-T

Variant names:

• chr19-38724693-C-T
• rs3786851
• NM_004924.6:c.2010+128C>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.2010+128C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 1,461,304 control chromosomes in the GnomAD database, including 151,433 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (12198 hom., cov: 32)
  • Exomes 𝑓: 0.45 (139235 hom.)
• Consequence: ACTN4 NM_004924.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.362
• Publications: 6 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 19-38724693-C-T is Benign according to our data. Variant chr19-38724693-C-T is described in ClinVar as Benign. ClinVar VariationId is 1183403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN4	NM_004924.6	c.2010+128C>T		intron_variant	Intron 16 of 20	ENST00000252699.7	NP_004915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7	c.2010+128C>T		intron_variant	Intron 16 of 20	1	NM_004924.6	ENSP00000252699.2

Frequencies

GnomAD3 genomes AF: 0.383 AC: 58203 AN: 151984 Hom.: 12207 Cov.: 32

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.435

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.498

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.369

GnomAD4 exome AF: 0.455 AC: 595580 AN: 1309202 Hom.: 139235 AF XY: 0.453 AC XY: 296777 AN XY: 655540

African (AFR) AF: 0.201 AC: 6186 AN: 30700

American (AMR) AF: 0.287 AC: 11551 AN: 40266

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 9830 AN: 24988

East Asian (EAS) AF: 0.523 AC: 19740 AN: 37710

South Asian (SAS) AF: 0.396 AC: 32186 AN: 81178

European-Finnish (FIN) AF: 0.477 AC: 17714 AN: 37140

Middle Eastern (MID) AF: 0.292 AC: 1279 AN: 4376

European-Non Finnish (NFE) AF: 0.474 AC: 473044 AN: 997278

Other (OTH) AF: 0.433 AC: 24050 AN: 55566

GnomAD4 genome AF: 0.383 AC: 58188 AN: 152102 Hom.: 12198 Cov.: 32 AF XY: 0.382 AC XY: 28418 AN XY: 74366

African (AFR) AF: 0.222 AC: 9200 AN: 41520

American (AMR) AF: 0.343 AC: 5251 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1412 AN: 3472

East Asian (EAS) AF: 0.436 AC: 2243 AN: 5150

South Asian (SAS) AF: 0.378 AC: 1826 AN: 4830

European-Finnish (FIN) AF: 0.498 AC: 5268 AN: 10570

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.466 AC: 31679 AN: 67946

Other (OTH) AF: 0.365 AC: 771 AN: 2114

Alfa AF: 0.417 Hom.: 2254

Bravo AF: 0.362

Asia WGS AF: 0.339 AC: 1179 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.6
DANN	Benign	0.58
PhyloP100		-0.36
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: rs3786851; hg19: chr19-39215333; COSMIC: COSV53149883; COSMIC: COSV53149883;