Genetic Variant PPP3CA:c.*42_*44dupTTT (chr4-101025820-C-CAAA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000944.5(PPP3CA):c.*42_*44dupTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0014 ( 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: Uncertain_significance. The variant received 0 ACMG points.

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.42_44dupTTT	3_prime_UTR	Exon 14 of 14	NP_000935.1	Q08209-1
PPP3CA	NM_001130691.2		c.42_44dupTTT	3_prime_UTR	Exon 13 of 13	NP_001124163.1	Q08209-2
PPP3CA	NM_001130692.2		c.42_44dupTTT	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.42_44dupTTT	3_prime_UTR	Exon 14 of 14	ENSP00000378323.3	Q08209-1
PPP3CA	ENST00000394853.8	TSL:1	c.42_44dupTTT	3_prime_UTR	Exon 13 of 13	ENSP00000378322.4	Q08209-2
PPP3CA	ENST00000323055.10	TSL:1	c.42_44dupTTT	3_prime_UTR	Exon 12 of 12	ENSP00000320580.6	Q08209-3

Frequencies

GnomAD3 genomes

AF:

0.000116

AC:

AN:

34562

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000252

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000933

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00144

AC:

638

AN:

444554

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

343

AN XY:

230174

show subpopulations

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

African (AFR)

AF:

0.000958

AC:

AN:

10440

American (AMR)

AF:

0.00148

AC:

AN:

16234

Ashkenazi Jewish (ASJ)

AF:

0.00189

AC:

AN:

7390

East Asian (EAS)

AF:

0.00291

AC:

AN:

15128

South Asian (SAS)

AF:

0.00304

AC:

106

AN:

34918

European-Finnish (FIN)

AF:

0.00135

AC:

AN:

23674

Middle Eastern (MID)

AF:

0.00130

AC:

AN:

1540

European-Non Finnish (NFE)

AF:

0.00118

AC:

375

AN:

317696

Other (OTH)

AF:

0.00177

AC:

AN:

17534

⚠️ 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: 0.316

Heterozygous variant carriers

105

157

210

262

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000116

AC:

AN:

34598

Hom.:

Cov.:

AF XY:

0.0000657

AC XY:

AN XY:

15224

show subpopulations

African (AFR)

AF:

0.000251

AC:

AN:

7966

American (AMR)

AF:

0.00

AC:

AN:

1876

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1164

East Asian (EAS)

AF:

0.00

AC:

AN:

446

South Asian (SAS)

AF:

0.00

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:

0.0000933

AC:

AN:

21438

Other (OTH)

AF:

0.00

AC:

AN:

400

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Splicing

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

Publications

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4-101025820-CAAAAAAAAAAAAAAAAAA-CAAAAAAAAAAAAAAAAAAAAA

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