rs28664200

Variant names:

• chr4-101330344-T-C
• rs28664200
• NM_000944.5:c.58+16395A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 13 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PPP3CA	NM_000944.5	c.58+16395A>G		intron_variant	Intron 1 of 13	ENST00000394854.8	NP_000935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP3CA	ENST00000394854.8	c.58+16395A>G		intron_variant	Intron 1 of 13	1	NM_000944.5	ENSP00000378323.3

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

GnomAD2 exomes AF: 0.343 AC: 62899 AN: 183276 AF XY: 0.340

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 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

African (AFR) AF: 0.222 AC: 1782 AN: 8024

American (AMR) AF: 0.458 AC: 11486 AN: 25070

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 2872 AN: 10542

East Asian (EAS) AF: 0.500 AC: 5743 AN: 11484

South Asian (SAS) AF: 0.407 AC: 23762 AN: 58382

European-Finnish (FIN) AF: 0.405 AC: 12460 AN: 30750

Middle Eastern (MID) AF: 0.195 AC: 532 AN: 2730

European-Non Finnish (NFE) AF: 0.282 AC: 48423 AN: 171664

Other (OTH) AF: 0.305 AC: 4460 AN: 14634

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

African (AFR) AF: 0.225 AC: 9277 AN: 41212

American (AMR) AF: 0.386 AC: 5834 AN: 15130

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 907 AN: 3462

East Asian (EAS) AF: 0.503 AC: 2489 AN: 4946

South Asian (SAS) AF: 0.426 AC: 1974 AN: 4632

European-Finnish (FIN) AF: 0.424 AC: 4397 AN: 10378

Middle Eastern (MID) AF: 0.159 AC: 46 AN: 290

European-Non Finnish (NFE) AF: 0.281 AC: 18999 AN: 67614

Other (OTH) AF: 0.293 AC: 618 AN: 2106

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
PhyloP100		-0.37
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: rs28664200; hg19: chr4-102251501; COSMIC: COSV59931001;