chr4-101032294-A-AAAGT

Variant names:

• chr4-101032294-A-AAAGT
• rs1553920379
• NM_000944.5:c.1308_1311dupACTT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000944.5(PPP3CA):​c.1308_1311dupACTT​(p.Ser438ThrfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L437L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP3CA NM_000944.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.610
• 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-101032294-A-AAAGT is Pathogenic according to our data. Variant chr4-101032294-A-AAAGT is described in ClinVar as Pathogenic. ClinVar VariationId is 522802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP3CA	NM_000944.5	MANE Select	c.1308_1311dupACTT	p.Ser438ThrfsTer14	frameshift	Exon 12 of 14	NP_000935.1
	PPP3CA	NM_001130691.2		c.1308_1311dupACTT	p.Ser438ThrfsTer20	frameshift	Exon 12 of 13	NP_001124163.1
	PPP3CA	NM_001130692.2		c.1182_1185dupACTT	p.Ser396ThrfsTer20	frameshift	Exon 11 of 12	NP_001124164.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP3CA	ENST00000394854.8	TSL:1 MANE Select	c.1308_1311dupACTT	p.Ser438ThrfsTer14	frameshift	Exon 12 of 14	ENSP00000378323.3
	PPP3CA	ENST00000394853.8	TSL:1	c.1308_1311dupACTT	p.Ser438ThrfsTer20	frameshift	Exon 12 of 13	ENSP00000378322.4
	PPP3CA	ENST00000323055.10	TSL:1	c.1182_1185dupACTT	p.Ser396ThrfsTer20	frameshift	Exon 11 of 12	ENSP00000320580.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy 91 Pathogenic:2

Nov 26, 2017

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshift mutation is categorized as deleterious according to ACMG guidelines (PMID: 18414213) and was found de novo in a 10-year-old male with epilepsy, developmental regression, global developmental delay, autism spectrum disorder, poor coordination, hyperreflexia with clonus, hypotonia, high pain threshold, high resting body temperature, and GI constipation and reflux.

May 24, 2025

Pediatric Department, Peking University First Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Pathogenic(PVS1+PS2+PM2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.61
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1553920379; hg19: chr4-101953451;