rs2287728

Positions:

• chr19-38704918-C-T

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.398-16C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0644 in 1,611,324 control chromosomes in the GnomAD database, including 3,696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (251 hom., cov: 33)
  • Exomes 𝑓: 0.065 (3445 hom.)
• Consequence: ACTN4 NM_004924.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.466

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]

LOC107985291 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-38704918-C-T is Benign according to our data. Variant chr19-38704918-C-T is described in ClinVar as [Benign]. Clinvar id is 259579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38704918-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0888 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN4	NM_004924.6	c.398-16C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000252699.7
LOC107985291	XR_001753937.2	n.170-2754G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN4	ENST00000252699.7	c.398-16C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004924.6	A1

Frequencies

GnomAD3 genomes AF: 0.0558 AC: 8485 AN: 152186 Hom.: 252 Cov.: 33

Gnomad AFR AF: 0.0484

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0578

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.0460

Gnomad SAS AF: 0.0965

Gnomad FIN AF: 0.0219

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0633

Gnomad OTH AF: 0.0583

GnomAD3 exomes AF: 0.0623 AC: 15652 AN: 251436 Hom.: 565 AF XY: 0.0639 AC XY: 8691 AN XY: 135904

Gnomad AFR exome AF: 0.0493

Gnomad AMR exome AF: 0.0678

Gnomad ASJ exome AF: 0.0604

Gnomad EAS exome AF: 0.0397

Gnomad SAS exome AF: 0.105

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.0621

Gnomad OTH exome AF: 0.0662

GnomAD4 exome AF: 0.0653 AC: 95220 AN: 1459020 Hom.: 3445 Cov.: 31 AF XY: 0.0662 AC XY: 48087 AN XY: 726130

Gnomad4 AFR exome AF: 0.0499

Gnomad4 AMR exome AF: 0.0709

Gnomad4 ASJ exome AF: 0.0622

Gnomad4 EAS exome AF: 0.0453

Gnomad4 SAS exome AF: 0.102

Gnomad4 FIN exome AF: 0.0251

Gnomad4 NFE exome AF: 0.0654

Gnomad4 OTH exome AF: 0.0652

GnomAD4 genome AF: 0.0557 AC: 8489 AN: 152304 Hom.: 251 Cov.: 33 AF XY: 0.0548 AC XY: 4084 AN XY: 74470

Gnomad4 AFR AF: 0.0484

Gnomad4 AMR AF: 0.0577

Gnomad4 ASJ AF: 0.0565

Gnomad4 EAS AF: 0.0461

Gnomad4 SAS AF: 0.0960

Gnomad4 FIN AF: 0.0219

Gnomad4 NFE AF: 0.0633

Gnomad4 OTH AF: 0.0591

Alfa AF: 0.0635 Hom.: 303

Bravo AF: 0.0584

Asia WGS AF: 0.0890 AC: 308 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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	-0.83
CADD	Benign	1.9
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2287728; hg19: chr19-39195558; COSMIC: COSV53148868; COSMIC: COSV53148868;