19-38647968-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004924.6(ACTN4):c.162+61T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.517 in 1,171,018 control chromosomes in the GnomAD database, including 151,168 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (11122 hom., cov: 24)
  • Exomes 𝑓: 0.53 (140046 hom.)
• Consequence: ACTN4 NM_004924.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.69

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-38647968-T-C is Benign according to our data. Variant chr19-38647968-T-C is described in ClinVar as [Benign]. Clinvar id is 1269337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN4	NM_004924.6	c.162+61T>C		intron_variant		ENST00000252699.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN4	ENST00000252699.7	c.162+61T>C		intron_variant		1	NM_004924.6	A1

Frequencies

GnomAD3 genomes AF: 0.411 AC: 52201 AN: 126904 Hom.: 11130 Cov.: 24

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.581

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.438

Gnomad EAS AF: 0.430

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.550

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.508

Gnomad OTH AF: 0.396

GnomAD4 exome AF: 0.530 AC: 553190 AN: 1044060 Hom.: 140046 Cov.: 21 AF XY: 0.526 AC XY: 267585 AN XY: 508268

Gnomad4 AFR exome AF: 0.142

Gnomad4 AMR exome AF: 0.310

Gnomad4 ASJ exome AF: 0.489

Gnomad4 EAS exome AF: 0.607

Gnomad4 SAS exome AF: 0.428

Gnomad4 FIN exome AF: 0.555

Gnomad4 NFE exome AF: 0.545

Gnomad4 OTH exome AF: 0.509

GnomAD4 genome AF: 0.411 AC: 52174 AN: 126958 Hom.: 11122 Cov.: 24 AF XY: 0.410 AC XY: 25287 AN XY: 61750

Gnomad4 AFR AF: 0.167

Gnomad4 AMR AF: 0.366

Gnomad4 ASJ AF: 0.438

Gnomad4 EAS AF: 0.429

Gnomad4 SAS AF: 0.437

Gnomad4 FIN AF: 0.550

Gnomad4 NFE AF: 0.508

Gnomad4 OTH AF: 0.393

Alfa AF: 0.311 Hom.: 796

Bravo AF: 0.323

Asia WGS AF: 0.302 AC: 1049 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Focal segmental glomerulosclerosis 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.59
Dann	Benign	0.50
RBP_binding_hub_radar		0.91
RBP_regulation_power_radar		3.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2303040; hg19: chr19-39138608; COSMIC: COSV53145998; COSMIC: COSV53145998;