4-101025820-CAAAAAAAAAAAAAAAAAA-CAAAAAA

Variant names:

• chr4-101025820-CAAAAAAAAAAAA-C
• rs35434632
• NM_000944.5:c.*33_*44delTTTTTTTTTTTT

Variant summary

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

The NM_000944.5(PPP3CA):​c.*33_*44delTTTTTTTTTTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000259 in 479,350 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_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 0.00040 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: PPP3CA NM_000944.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.89
• 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 14 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.*33_*44delTTTTTTTTTTTT		3_prime_UTR	Exon 14 of 14	NP_000935.1	Q08209-1
	PPP3CA	NM_001130691.2		c.*33_*44delTTTTTTTTTTTT		3_prime_UTR	Exon 13 of 13	NP_001124163.1	Q08209-2
	PPP3CA	NM_001130692.2		c.*33_*44delTTTTTTTTTTTT		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.*33_*44delTTTTTTTTTTTT		3_prime_UTR	Exon 14 of 14	ENSP00000378323.3	Q08209-1
	PPP3CA	ENST00000394853.8	TSL:1	c.*33_*44delTTTTTTTTTTTT		3_prime_UTR	Exon 13 of 13	ENSP00000378322.4	Q08209-2
	PPP3CA	ENST00000323055.10	TSL:1	c.*33_*44delTTTTTTTTTTTT		3_prime_UTR	Exon 12 of 12	ENSP00000320580.6	Q08209-3

Frequencies

GnomAD3 genomes AF: 0.000405 AC: 14 AN: 34568 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000378

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00226

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000466

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000247 AC: 110 AN: 444782 Hom.: 0 AF XY: 0.000217 AC XY: 50 AN XY: 230296

African (AFR) AF: 0.000383 AC: 4 AN: 10438

American (AMR) AF: 0.000123 AC: 2 AN: 16238

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

East Asian (EAS) AF: 0.000264 AC: 4 AN: 15138

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: 0.000299 AC: 95 AN: 317862

Other (OTH) AF: 0.000228 AC: 4 AN: 17544

GnomAD4 genome AF: 0.000405 AC: 14 AN: 34568 Hom.: 0 Cov.: 0 AF XY: 0.000329 AC XY: 5 AN XY: 15202

African (AFR) AF: 0.000378 AC: 3 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: 0.00226 AC: 1 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: 0.000466 AC: 10 AN: 21442

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

Alfa AF: 0.00 Hom.: 53

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=99/1	polymorphism

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;