19-38701093-C-T

Position:

• chr19-38701093-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004924.6(ACTN4):​c.369C>T​(p.Gly123=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0126 in 1,614,090 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (5 hom., cov: 32)
  • Exomes 𝑓: 0.013 (153 hom.)
• Consequence: ACTN4 NM_004924.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -6.54

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 19-38701093-C-T is Benign according to our data. Variant chr19-38701093-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.54 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00832 (1267/152318) while in subpopulation NFE AF= 0.0131 (893/68030). AF 95% confidence interval is 0.0124. There are 5 homozygotes in gnomad4. There are 592 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1267 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN4	NM_004924.6	c.369C>T	p.Gly123=	synonymous_variant	3/21	ENST00000252699.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN4	ENST00000252699.7	c.369C>T	p.Gly123=	synonymous_variant	3/21	1	NM_004924.6	A1

Frequencies

GnomAD3 genomes AF: 0.00832 AC: 1267 AN: 152200 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0165

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0131

Gnomad OTH AF: 0.00911

GnomAD3 exomes AF: 0.00895 AC: 2250 AN: 251426 Hom.: 26 AF XY: 0.00889 AC XY: 1208 AN XY: 135900

Gnomad AFR exome AF: 0.00301

Gnomad AMR exome AF: 0.00370

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.0163

Gnomad NFE exome AF: 0.0144

Gnomad OTH exome AF: 0.00864

GnomAD4 exome AF: 0.0131 AC: 19133 AN: 1461772 Hom.: 153 Cov.: 32 AF XY: 0.0127 AC XY: 9244 AN XY: 727186

Gnomad4 AFR exome AF: 0.00257

Gnomad4 AMR exome AF: 0.00405

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00103

Gnomad4 FIN exome AF: 0.0155

Gnomad4 NFE exome AF: 0.0156

Gnomad4 OTH exome AF: 0.00929

GnomAD4 genome AF: 0.00832 AC: 1267 AN: 152318 Hom.: 5 Cov.: 32 AF XY: 0.00795 AC XY: 592 AN XY: 74486

Gnomad4 AFR AF: 0.00296

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0165

Gnomad4 NFE AF: 0.0131

Gnomad4 OTH AF: 0.00901

Alfa AF: 0.0115 Hom.: 7

Bravo AF: 0.00759

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0106

EpiControl AF: 0.0117

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ACTN4: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Focal segmental glomerulosclerosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2020

- -

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	-0.61
CADD	Benign	2.7
DANN	Benign	0.91
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs140381330; hg19: chr19-39191733;