chr4-101032267-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000944.5(PPP3CA):c.1339G>A(p.Ala447Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,146 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PPP3CA
NM_000944.5 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.62

Publications

0 publications found

Variant links:

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

PPP3CA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 4-101032267-C-T is Pathogenic according to our data. Variant chr4-101032267-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 441273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP3CA	NM_000944.5 link	c.1339G>A	p.Ala447Thr	missense_variant, splice_region_variant	Exon 12 of 14	ENST00000394854.8	NP_000935.1	Q08209-1A0A0S2Z4C6
PPP3CA	NM_001130691.2 link	c.1339G>A	p.Ala447Thr	missense_variant, splice_region_variant	Exon 12 of 13		NP_001124163.1	Q08209-2A0A0S2Z4B5
PPP3CA	NM_001130692.2 link	c.1213G>A	p.Ala405Thr	missense_variant, splice_region_variant	Exon 11 of 12		NP_001124164.1	Q08209-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP3CA	ENST00000394854.8 link	c.1339G>A	p.Ala447Thr	missense_variant, splice_region_variant	Exon 12 of 14	1	NM_000944.5	ENSP00000378323.3		Q08209-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1443146

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717110

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32592

American (AMR)

AF:

0.00

AC:

AN:

41426

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25216

East Asian (EAS)

AF:

0.00

AC:

AN:

38936

South Asian (SAS)

AF:

0.00

AC:

AN:

82900

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52976

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

9.06e-7

AC:

AN:

1103880

Other (OTH)

AF:

0.00

AC:

AN:

59542

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy 91

Pathogenic:3

Jan 09, 2025

Department of Neurology, Zibo Changguo Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM6_Strong, PM1, PM5, PM2_Supporting, PP2 -

Mar 15, 2021

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 23, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.61). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PPP3CA related disorder (ClinVar ID: VCV000441273 / PMID: 28942967). The variant has been previously reported as de novo in a similarly affected individual (PMID: 28942967). A different missense change at the same codon (p.Ala447Ser) has been reported to be associated with PPP3CA related disorder (PMID: 32238909). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:2

Feb 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 447 of the PPP3CA protein (p.Ala447Thr). This variant also falls at the last nucleotide of exon 12, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with developmental and epileptic encephalopathy (DEE) (PMID: 28942967). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 441273). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PPP3CA: PM2, PS2:Moderate, PM5:Supporting, PP2, PP3, PS4:Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Uncertain

0.096

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

.;T;.;.;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Benign

0.022

MetaRNN

Uncertain

0.47

T;T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.8

.;M;.;M;.

PhyloP100

7.6

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.3

N;N;D;D;N

REVEL

Benign

0.23

Sift

Benign

0.25

T;T;T;T;T

Sift4G

Benign

0.081

T;T;T;T;T

Polyphen

1.0, 0.19

.;D;.;B;.

Vest4

0.65

MutPred

0.41

.;Gain of catalytic residue at A447 (P = 0.0402);.;Gain of catalytic residue at A447 (P = 0.0402);.;

MVP

0.61

MPC

1.8

ClinPred

0.99

GERP RS

5.4

Varity_R

0.21

gMVP

0.83

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.61

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.61

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over