rs28664200

chr4-101330344-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000944.5(PPP3CA):c.58+16395A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 483,962 control chromosomes in the GnomAD database, including 27,126 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.30 (7149 hom., cov: 31)
  • Exomes 𝑓: 0.33 (19977 hom.)
• Consequence: PPP3CA NM_000944.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.374

Genes affected

PPP3CA (HGNC:9314): (protein phosphatase 3 catalytic subunit alpha) Enables several functions, including ATPase binding activity; calmodulin binding activity; and calmodulin-dependent protein phosphatase activity. Involved in several processes, including calcineurin-NFAT signaling cascade; peptidyl-serine dephosphorylation; and response to calcium ion. Located in several cellular components, including cytosol; dendritic spine; and nucleoplasm. Part of calcineurin complex. Colocalizes with cytoplasmic side of plasma membrane. Implicated in developmental and epileptic encephalopathy 91. Biomarker of focal segmental glomerulosclerosis and schizophrenia. [provided by Alliance of Genome Resources, Apr 2022]

MIR1255A (HGNC:35320): (microRNA 1255a) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP3CA	NM_000944.5	c.58+16395A>G		intron_variant		ENST00000394854.8
MIR1255A	NR_031656.1	n.71A>G		non_coding_transcript_exon_variant	1/1
PPP3CA	NM_001130691.2	c.58+16395A>G		intron_variant
PPP3CA	NM_001130692.2	c.58+16395A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP3CA	ENST00000394854.8	c.58+16395A>G		intron_variant		1	NM_000944.5	P3
MIR1255A	ENST00000408338.1	n.71A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.298 AC: 44866 AN: 150558 Hom.: 7136 Cov.: 31

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.504

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.424

Gnomad MID AF: 0.163

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.286

GnomAD3 exomes AF: 0.343 AC: 62899 AN: 183276 Hom.: 11665 AF XY: 0.340 AC XY: 33854 AN XY: 99710

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.459

Gnomad ASJ exome AF: 0.274

Gnomad EAS exome AF: 0.503

Gnomad SAS exome AF: 0.410

Gnomad FIN exome AF: 0.410

Gnomad NFE exome AF: 0.277

Gnomad OTH exome AF: 0.310

GnomAD4 exome AF: 0.335 AC: 111520 AN: 333280 Hom.: 19977 Cov.: 0 AF XY: 0.337 AC XY: 64298 AN XY: 190800

Gnomad4 AFR exome AF: 0.222

Gnomad4 AMR exome AF: 0.458

Gnomad4 ASJ exome AF: 0.272

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.407

Gnomad4 FIN exome AF: 0.405

Gnomad4 NFE exome AF: 0.282

Gnomad4 OTH exome AF: 0.305

GnomAD4 genome AF: 0.298 AC: 44907 AN: 150682 Hom.: 7149 Cov.: 31 AF XY: 0.311 AC XY: 22909 AN XY: 73634

Gnomad4 AFR AF: 0.225

Gnomad4 AMR AF: 0.386

Gnomad4 ASJ AF: 0.262

Gnomad4 EAS AF: 0.503

Gnomad4 SAS AF: 0.426

Gnomad4 FIN AF: 0.424

Gnomad4 NFE AF: 0.281

Gnomad4 OTH AF: 0.293

Alfa AF: 0.275 Hom.: 2541

Bravo AF: 0.293

Asia WGS AF: 0.477 AC: 1656 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	2.1
Dann	Benign	0.57

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: rs28664200; hg19: chr4-102251501; COSMIC: COSV59931001;