rs1395475

Variant names:

• chr4-101194029-C-T
• rs1395475
• NM_000944.5:c.259+1887G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000944.5(PPP3CA):​c.259+1887G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 151,978 control chromosomes in the GnomAD database, including 7,186 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 0.25 (7186 hom., cov: 32)
• Consequence: PPP3CA NM_000944.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.517
• Publications: 6 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]

PPP3CA Gene-Disease associations (from GenCC):

• arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• developmental and epileptic encephalopathy 91

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP3CA	NM_000944.5	c.259+1887G>A		intron_variant	Intron 2 of 13	ENST00000394854.8	NP_000935.1
PPP3CA	NM_001130691.2	c.259+1887G>A		intron_variant	Intron 2 of 12		NP_001124163.1
PPP3CA	NM_001130692.2	c.259+1887G>A		intron_variant	Intron 2 of 11		NP_001124164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP3CA	ENST00000394854.8	c.259+1887G>A		intron_variant	Intron 2 of 13	1	NM_000944.5	ENSP00000378323.3

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37186 AN: 151860 Hom.: 7161 Cov.: 32

Gnomad AFR AF: 0.520

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.304

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0938

Gnomad OTH AF: 0.236

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.245 AC: 37260 AN: 151978 Hom.: 7186 Cov.: 32 AF XY: 0.247 AC XY: 18317 AN XY: 74302

African (AFR) AF: 0.520 AC: 21553 AN: 41410

American (AMR) AF: 0.305 AC: 4646 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 450 AN: 3466

East Asian (EAS) AF: 0.265 AC: 1370 AN: 5168

South Asian (SAS) AF: 0.139 AC: 667 AN: 4810

European-Finnish (FIN) AF: 0.150 AC: 1582 AN: 10560

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0938 AC: 6378 AN: 67988

Other (OTH) AF: 0.233 AC: 493 AN: 2114

Alfa AF: 0.160 Hom.: 6571

Bravo AF: 0.273

Asia WGS AF: 0.187 AC: 651 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.9
DANN	Benign	0.66
PhyloP100		-0.52
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: rs1395475; hg19: chr4-102115186;