4-101025820-CAAAAAAAAAAAAAAAAAA-CAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA

Variant names:

• chr4-101025820-C-CAAAAAAAAAAAAAAAAAAA
• rs35434632
• NM_000944.5:c.*26_*44dupTTTTTTTTTTTTTTTTTTT

Variant summary

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

The NM_000944.5(PPP3CA):​c.*26_*44dupTTTTTTTTTTTTTTTTTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PPP3CA NM_000944.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0900
• Publications: 0 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.*26_*44dupTTTTTTTTTTTTTTTTTTT		3_prime_UTR	Exon 14 of 14	NP_000935.1	Q08209-1
	PPP3CA	NM_001130691.2		c.*26_*44dupTTTTTTTTTTTTTTTTTTT		3_prime_UTR	Exon 13 of 13	NP_001124163.1	Q08209-2
	PPP3CA	NM_001130692.2		c.*26_*44dupTTTTTTTTTTTTTTTTTTT		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.*26_*44dupTTTTTTTTTTTTTTTTTTT		3_prime_UTR	Exon 14 of 14	ENSP00000378323.3	Q08209-1
	PPP3CA	ENST00000394853.8	TSL:1	c.*26_*44dupTTTTTTTTTTTTTTTTTTT		3_prime_UTR	Exon 13 of 13	ENSP00000378322.4	Q08209-2
	PPP3CA	ENST00000323055.10	TSL:1	c.*26_*44dupTTTTTTTTTTTTTTTTTTT		3_prime_UTR	Exon 12 of 12	ENSP00000320580.6	Q08209-3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 34564 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000225 AC: 1 AN: 444800 Hom.: 0 Cov.: 0 AF XY: 0.00000434 AC XY: 1 AN XY: 230308

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

African (AFR) AF: 0.00 AC: 0 AN: 10440

American (AMR) AF: 0.00 AC: 0 AN: 16238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7394

East Asian (EAS) AF: 0.00 AC: 0 AN: 15140

South Asian (SAS) AF: 0.0000286 AC: 1 AN: 34952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1540

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 317876

Other (OTH) AF: 0.00 AC: 0 AN: 17544

⚠️ 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: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 34564 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 15202

African (AFR) AF: 0.00 AC: 0 AN: 7946

American (AMR) AF: 0.00 AC: 0 AN: 1870

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1164

East Asian (EAS) AF: 0.00 AC: 0 AN: 442

South Asian (SAS) AF: 0.00 AC: 0 AN: 538

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: 0.00 AC: 0 AN: 21438

Other (OTH) AF: 0.00 AC: 0 AN: 398

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

Other links and lift over

dbSNP: rs35434632; hg19: chr4-101946977;