4-101025820-CAAAAAAAAAAAAAAAAAA-CAAAAAAAAAAAAAAAAAAA

Variant names:

• chr4-101025820-C-CA
• rs35434632
• NM_000944.5:c.*44dupT

Variant summary

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

The NM_000944.5(PPP3CA):​c.*44dupT 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 0.037 (148 hom., cov: 0)
  • Exomes 𝑓: 0.018 (1 hom.)
  • Failed GnomAD Quality Control
• 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: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP3CA	NM_000944.5	MANE Select	c.*44dupT		3_prime_UTR	Exon 14 of 14	NP_000935.1	Q08209-1
	PPP3CA	NM_001130691.2		c.*44dupT		3_prime_UTR	Exon 13 of 13	NP_001124163.1	Q08209-2
	PPP3CA	NM_001130692.2		c.*44dupT		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.*44dupT		3_prime_UTR	Exon 14 of 14	ENSP00000378323.3	Q08209-1
	PPP3CA	ENST00000394853.8	TSL:1	c.*44dupT		3_prime_UTR	Exon 13 of 13	ENSP00000378322.4	Q08209-2
	PPP3CA	ENST00000323055.10	TSL:1	c.*44dupT		3_prime_UTR	Exon 12 of 12	ENSP00000320580.6	Q08209-3

Frequencies

GnomAD3 genomes AF: 0.0369 AC: 1277 AN: 34584 Hom.: 148 Cov.: 0

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.0178

Gnomad AMR AF: 0.0423

Gnomad ASJ AF: 0.0875

Gnomad EAS AF: 0.0227

Gnomad SAS AF: 0.0448

Gnomad FIN AF: 0.00291

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0428

Gnomad OTH AF: 0.0427

GnomAD2 exomes AF: 0.00562 AC: 239 AN: 42522 AF XY: 0.00603

Gnomad AFR exome AF: 0.00603

Gnomad AMR exome AF: 0.0177

Gnomad ASJ exome AF: 0.00612

Gnomad EAS exome AF: 0.0101

Gnomad FIN exome AF: 0.000671

Gnomad NFE exome AF: 0.00257

Gnomad OTH exome AF: 0.00906

GnomAD4 exome AF: 0.0180 AC: 8002 AN: 443448 Hom.: 1 Cov.: 0 AF XY: 0.0182 AC XY: 4189 AN XY: 229640

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

African (AFR) AF: 0.0142 AC: 148 AN: 10412

American (AMR) AF: 0.0143 AC: 232 AN: 16202

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 142 AN: 7364

East Asian (EAS) AF: 0.0306 AC: 461 AN: 15068

South Asian (SAS) AF: 0.0204 AC: 713 AN: 34876

European-Finnish (FIN) AF: 0.0138 AC: 326 AN: 23608

Middle Eastern (MID) AF: 0.0170 AC: 26 AN: 1530

European-Non Finnish (NFE) AF: 0.0178 AC: 5627 AN: 316922

Other (OTH) AF: 0.0187 AC: 327 AN: 17466

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0369 AC: 1277 AN: 34620 Hom.: 148 Cov.: 0 AF XY: 0.0363 AC XY: 553 AN XY: 15234

African (AFR) AF: 0.0143 AC: 114 AN: 7968

American (AMR) AF: 0.0422 AC: 79 AN: 1874

Ashkenazi Jewish (ASJ) AF: 0.0875 AC: 102 AN: 1166

East Asian (EAS) AF: 0.0225 AC: 10 AN: 444

South Asian (SAS) AF: 0.0446 AC: 24 AN: 538

European-Finnish (FIN) AF: 0.00291 AC: 1 AN: 344

Middle Eastern (MID) AF: 0.133 AC: 4 AN: 30

European-Non Finnish (NFE) AF: 0.0428 AC: 919 AN: 21462

Other (OTH) AF: 0.0425 AC: 17 AN: 400

Alfa AF: 0.00416 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

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

Other links and lift over

dbSNP: rs35434632; hg19: chr4-101946977;