Genetic Variant PPP3CA:c.*43_*44dupTT (chr4-101025820-C-CAA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000944.5(PPP3CA):c.*43_*44dupTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0048 ( 0 hom. )

Consequence

PPP3CA
NM_000944.5 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0900

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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 50 AD gene.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PPP3CA	NM_000944.5	MANE Select	c.43_44dupTT	3_prime_UTR	Exon 14 of 14	NP_000935.1	Q08209-1
PPP3CA	NM_001130691.2		c.43_44dupTT	3_prime_UTR	Exon 13 of 13	NP_001124163.1	Q08209-2
PPP3CA	NM_001130692.2		c.43_44dupTT	3_prime_UTR	Exon 12 of 12	NP_001124164.1	Q08209-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PPP3CA	ENST00000394854.8	TSL:1 MANE Select	c.43_44dupTT	3_prime_UTR	Exon 14 of 14	ENSP00000378323.3	Q08209-1
PPP3CA	ENST00000394853.8	TSL:1	c.43_44dupTT	3_prime_UTR	Exon 13 of 13	ENSP00000378322.4	Q08209-2
PPP3CA	ENST00000323055.10	TSL:1	c.43_44dupTT	3_prime_UTR	Exon 12 of 12	ENSP00000320580.6	Q08209-3

Frequencies

GnomAD3 genomes

AF:

0.00145

AC:

AN:

34558

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00160

Gnomad ASJ

AF:

0.000859

Gnomad EAS

AF:

0.00455

Gnomad SAS

AF:

0.00558

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00149

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00475

AC:

2109

AN:

443964

Hom.:

Cov.:

AF XY:

0.00481

AC XY:

1106

AN XY:

229910

show subpopulations

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

African (AFR)

AF:

0.00393

AC:

AN:

10428

American (AMR)

AF:

0.00512

AC:

AN:

16214

Ashkenazi Jewish (ASJ)

AF:

0.00677

AC:

AN:

7386

East Asian (EAS)

AF:

0.00874

AC:

132

AN:

15100

South Asian (SAS)

AF:

0.00776

AC:

271

AN:

34910

European-Finnish (FIN)

AF:

0.00296

AC:

AN:

23650

Middle Eastern (MID)

AF:

0.00456

AC:

AN:

1536

European-Non Finnish (NFE)

AF:

0.00432

AC:

1372

AN:

317238

Other (OTH)

AF:

0.00474

AC:

AN:

17502

⚠️ 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: 0.330

Heterozygous variant carriers

159

318

478

637

796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

132

176

220

<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:

0.00145

AC:

AN:

34594

Hom.:

Cov.:

AF XY:

0.00151

AC XY:

AN XY:

15224

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

7964

American (AMR)

AF:

0.00160

AC:

AN:

1878

Ashkenazi Jewish (ASJ)

AF:

0.000859

AC:

AN:

1164

East Asian (EAS)

AF:

0.00450

AC:

AN:

444

South Asian (SAS)

AF:

0.00556

AC:

AN:

540

European-Finnish (FIN)

AF:

0.00

AC:

AN:

344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00149

AC:

AN:

21436

Other (OTH)

AF:

0.00

AC:

AN:

400

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.595

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.090

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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4-101025820-CAAAAAAAAAAAAAAAAAA-CAAAAAAAAAAAAAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over