NM_000944.5:c.249G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000944.5(PPP3CA):c.249G>A(p.Ala83Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,613,482 control chromosomes in the GnomAD database, including 1,755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A83A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.062 ( 953 hom., cov: 32)

Exomes 𝑓: 0.0086 ( 802 hom. )

Consequence

PPP3CA
NM_000944.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -3.05

Publications

7 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 4-101195926-C-T is Benign according to our data. Variant chr4-101195926-C-T is described in ClinVar as Benign. ClinVar VariationId is 1290046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.05 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP3CA	NM_000944.5 link	c.249G>A	p.Ala83Ala	synonymous_variant	Exon 2 of 14	ENST00000394854.8	NP_000935.1	Q08209-1A0A0S2Z4C6
PPP3CA	NM_001130691.2 link	c.249G>A	p.Ala83Ala	synonymous_variant	Exon 2 of 13		NP_001124163.1	Q08209-2A0A0S2Z4B5
PPP3CA	NM_001130692.2 link	c.249G>A	p.Ala83Ala	synonymous_variant	Exon 2 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.249G>A	p.Ala83Ala	synonymous_variant	Exon 2 of 14	1	NM_000944.5	ENSP00000378323.3		Q08209-1

Frequencies

GnomAD3 genomes

AF:

0.0619

AC:

9414

AN:

152046

Hom.:

951

Cov.:

show subpopulations

Gnomad AFR

AF:

0.205

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0284

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.0351

Gnomad SAS

AF:

0.0139

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00215

Gnomad OTH

AF:

0.0407

GnomAD2 exomes

AF:

0.0211

AC:

5297

AN:

250614

AF XY:

0.0169

show subpopulations

Gnomad AFR exome

AF:

0.211

Gnomad AMR exome

AF:

0.0142

Gnomad ASJ exome

AF:

0.00120

Gnomad EAS exome

AF:

0.0436

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00215

Gnomad OTH exome

AF:

0.0113

GnomAD4 exome

AF:

0.00858

AC:

12545

AN:

1461318

Hom.:

802

Cov.:

AF XY:

0.00794

AC XY:

5769

AN XY:

726942

show subpopulations

African (AFR)

AF:

0.206

AC:

6904

AN:

33446

American (AMR)

AF:

0.0160

AC:

715

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.000997

AC:

AN:

26086

East Asian (EAS)

AF:

0.0239

AC:

947

AN:

39684

South Asian (SAS)

AF:

0.00809

AC:

697

AN:

86186

European-Finnish (FIN)

AF:

0.0000750

AC:

AN:

53360

Middle Eastern (MID)

AF:

0.0224

AC:

129

AN:

5762

European-Non Finnish (NFE)

AF:

0.00181

AC:

2014

AN:

1111730

Other (OTH)

AF:

0.0184

AC:

1109

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

533

1067

1600

2134

2667

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

282

564

846

1128

1410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0620

AC:

9440

AN:

152164

Hom.:

953

Cov.:

AF XY:

0.0595

AC XY:

4424

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.205

AC:

8518

AN:

41464

American (AMR)

AF:

0.0283

AC:

432

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3466

East Asian (EAS)

AF:

0.0352

AC:

182

AN:

5176

South Asian (SAS)

AF:

0.0139

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00215

AC:

146

AN:

68020

Other (OTH)

AF:

0.0402

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

378

756

1135

1513

1891

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

270

360

450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0247

Hom.:

213

Bravo

AF:

0.0712

Asia WGS

AF:

0.0300

AC:

104

AN:

3478

EpiCase

AF:

0.00284

EpiControl

AF:

0.00303

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

5.7

(source)

DANN

Benign

0.60

PhyloP100

-3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over