4-101083203-G-C

Variant names:

• chr4-101083203-G-C
• rs199706529
• NM_000944.5:c.843C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000944.5(PPP3CA):​c.843C>G​(p.His281Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. H281H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP3CA NM_000944.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.767
• Publications: 2 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000944.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 4-101083203-G-C is Pathogenic according to our data. Variant chr4-101083203-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 441274.Status of the report is criteria_provided_single_submitter, 1 stars.

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.843C>G	p.His281Gln	missense	Exon 7 of 14	NP_000935.1
	PPP3CA	NM_001130691.2		c.843C>G	p.His281Gln	missense	Exon 7 of 13	NP_001124163.1
	PPP3CA	NM_001130692.2		c.843C>G	p.His281Gln	missense	Exon 7 of 12	NP_001124164.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP3CA	ENST00000394854.8	TSL:1 MANE Select	c.843C>G	p.His281Gln	missense	Exon 7 of 14	ENSP00000378323.3
	PPP3CA	ENST00000394853.8	TSL:1	c.843C>G	p.His281Gln	missense	Exon 7 of 13	ENSP00000378322.4
	PPP3CA	ENST00000323055.10	TSL:1	c.843C>G	p.His281Gln	missense	Exon 7 of 12	ENSP00000320580.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy 91 Pathogenic:2

Jan 03, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4_Supporting, PM1, PM2, PM6, PP2, PP3

Mar 15, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	5.1	H
PhyloP100		0.77
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.89		Loss of catalytic residue at R279 (P = 0.1053)
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		-1.6
Varity_R		0.96
gMVP		0.96
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199706529; hg19: chr4-102004360;