NM_000944.5:c.275A>G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000944.5(PPP3CA):c.275A>G(p.His92Arg) variant causes a missense change involving the alteration of a 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H92D) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PPP3CA
NM_000944.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.73

Publications

1 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-101109064-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 3252473.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.908

PP5

Variant 4-101109063-T-C is Pathogenic according to our data. Variant chr4-101109063-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 441272.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.275A>G	p.His92Arg	missense_variant	Exon 3 of 14	ENST00000394854.8	NP_000935.1	Q08209-1A0A0S2Z4C6
PPP3CA	NM_001130691.2 link	c.275A>G	p.His92Arg	missense_variant	Exon 3 of 13		NP_001124163.1	Q08209-2A0A0S2Z4B5
PPP3CA	NM_001130692.2 link	c.275A>G	p.His92Arg	missense_variant	Exon 3 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.275A>G	p.His92Arg	missense_variant	Exon 3 of 14	1	NM_000944.5	ENSP00000378323.3		Q08209-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461134

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726946

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111462

Other (OTH)

AF:

0.00

AC:

AN:

60356

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy 91

Pathogenic:2

Mar 15, 2021

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 24, 2025

Pediatric Department, Peking University First Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Likely pathogenic(PS2, PM2_Supporting, PP3) -

Inborn genetic diseases

Pathogenic:1

Feb 21, 2018

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Seizure;C3714756:Intellectual disability

Pathogenic:1

Feb 25, 2020

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

De novo variant, absent from gnomAD, previously described. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;.;.;D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.91

D;D;D;D;D

MetaSVM

Uncertain

0.35

MutationAssessor

Pathogenic

4.2

H;H;H;.;.

PhyloP100

7.7

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-7.8

D;D;D;D;D

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Uncertain

0.025

D;D;D;D;D

Polyphen

1.0

D;.;D;.;.

Vest4

0.96

MutPred

0.73

Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;.;

MVP

0.85

MPC

2.5

ClinPred

1.0

GERP RS

5.1

Varity_R

0.99

gMVP

1.0

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

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