4-101257806-T-G

Variant names:

• chr4-101257806-T-G
• rs2850965
• NM_000944.5:c.59-61690A>C

Variant summary

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

The NM_000944.5(PPP3CA):​c.59-61690A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0839 in 152,182 control chromosomes in the GnomAD database, including 727 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 0.084 (727 hom., cov: 32)
• Consequence: PPP3CA NM_000944.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.56
• Publications: 7 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000944.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP3CA	NM_000944.5	MANE Select	c.59-61690A>C		intron	N/A	NP_000935.1
	PPP3CA	NM_001130691.2		c.59-61690A>C		intron	N/A	NP_001124163.1
	PPP3CA	NM_001130692.2		c.59-61690A>C		intron	N/A	NP_001124164.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP3CA	ENST00000394854.8	TSL:1 MANE Select	c.59-61690A>C		intron	N/A	ENSP00000378323.3
	PPP3CA	ENST00000394853.8	TSL:1	c.59-61690A>C		intron	N/A	ENSP00000378322.4
	PPP3CA	ENST00000323055.10	TSL:1	c.59-61690A>C		intron	N/A	ENSP00000320580.6

Frequencies

GnomAD3 genomes AF: 0.0838 AC: 12737 AN: 152064 Hom.: 717 Cov.: 32

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0828

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.0524

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.106

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

GnomAD4 genome AF: 0.0839 AC: 12764 AN: 152182 Hom.: 727 Cov.: 32 AF XY: 0.0825 AC XY: 6142 AN XY: 74426

African (AFR) AF: 0.0283 AC: 1176 AN: 41550

American (AMR) AF: 0.0828 AC: 1262 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 557 AN: 3468

East Asian (EAS) AF: 0.164 AC: 850 AN: 5178

South Asian (SAS) AF: 0.146 AC: 705 AN: 4830

European-Finnish (FIN) AF: 0.0524 AC: 556 AN: 10612

Middle Eastern (MID) AF: 0.120 AC: 35 AN: 292

European-Non Finnish (NFE) AF: 0.108 AC: 7352 AN: 67974

Other (OTH) AF: 0.112 AC: 236 AN: 2116

Alfa AF: 0.0973 Hom.: 678

Bravo AF: 0.0826

Asia WGS AF: 0.154 AC: 533 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.35
DANN	Benign	0.59
PhyloP100		-2.6
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: rs2850965; hg19: chr4-102178963;