4-101025820-CAAAAAAAAAAAAAAAAAA-CAAAAAAAAAAAAAAAAAAAA

Variant names:

• chr4-101025820-C-CAA
• rs35434632
• NM_000944.5:c.*43_*44dupTT

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0900
• Publications: 1 publications found

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

ACMG classification

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	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: 50 AN: 34558 Hom.: 0 Cov.: 0

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.: 0 Cov.: 0 AF XY: 0.00481 AC XY: 1106 AN XY: 229910

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

African (AFR) AF: 0.00393 AC: 41 AN: 10428

American (AMR) AF: 0.00512 AC: 83 AN: 16214

Ashkenazi Jewish (ASJ) AF: 0.00677 AC: 50 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: 70 AN: 23650

Middle Eastern (MID) AF: 0.00456 AC: 7 AN: 1536

European-Non Finnish (NFE) AF: 0.00432 AC: 1372 AN: 317238

Other (OTH) AF: 0.00474 AC: 83 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.

GnomAD4 genome AF: 0.00145 AC: 50 AN: 34594 Hom.: 0 Cov.: 0 AF XY: 0.00151 AC XY: 23 AN XY: 15224

African (AFR) AF: 0.00113 AC: 9 AN: 7964

American (AMR) AF: 0.00160 AC: 3 AN: 1878

Ashkenazi Jewish (ASJ) AF: 0.000859 AC: 1 AN: 1164

East Asian (EAS) AF: 0.00450 AC: 2 AN: 444

South Asian (SAS) AF: 0.00556 AC: 3 AN: 540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 30

European-Non Finnish (NFE) AF: 0.00149 AC: 32 AN: 21436

Other (OTH) AF: 0.00 AC: 0 AN: 400

Alfa AF: 0.00 Hom.: 53

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.090
Mutation Taster		=100/0	polymorphism

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs35434632; hg19: chr4-101946977;