4-101170174-CAAAAG-C

Variant names:

• chr4-101170174-CAAAAG-C
• rs45625639
• NM_000944.5:c.259+25737_259+25741delCTTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000944.5(PPP3CA):​c.259+25737_259+25741delCTTTT variant causes a intron 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 0.49 (19326 hom., cov: 0)
• Consequence: PPP3CA NM_000944.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.426
• 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: Labcorp Genetics (formerly Invitae), Orphanet, 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.599 is higher than 0.05.

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.259+25737_259+25741delCTTTT		intron	N/A	NP_000935.1	Q08209-1
	PPP3CA	NM_001130691.2		c.259+25737_259+25741delCTTTT		intron	N/A	NP_001124163.1	Q08209-2
	PPP3CA	NM_001130692.2		c.259+25737_259+25741delCTTTT		intron	N/A	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.259+25737_259+25741delCTTTT		intron	N/A	ENSP00000378323.3	Q08209-1
	PPP3CA	ENST00000394853.8	TSL:1	c.259+25737_259+25741delCTTTT		intron	N/A	ENSP00000378322.4	Q08209-2
	PPP3CA	ENST00000323055.10	TSL:1	c.259+25737_259+25741delCTTTT		intron	N/A	ENSP00000320580.6	Q08209-3

Frequencies

GnomAD3 genomes AF: 0.488 AC: 73810 AN: 151212 Hom.: 19324 Cov.: 0

Gnomad AFR AF: 0.311

Gnomad AMI AF: 0.712

Gnomad AMR AF: 0.419

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.284

Gnomad SAS AF: 0.492

Gnomad FIN AF: 0.629

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.604

Gnomad OTH AF: 0.498

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.488 AC: 73804 AN: 151328 Hom.: 19326 Cov.: 0 AF XY: 0.485 AC XY: 35857 AN XY: 73890

African (AFR) AF: 0.311 AC: 12838 AN: 41308

American (AMR) AF: 0.418 AC: 6357 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.432 AC: 1497 AN: 3462

East Asian (EAS) AF: 0.284 AC: 1457 AN: 5122

South Asian (SAS) AF: 0.492 AC: 2368 AN: 4812

European-Finnish (FIN) AF: 0.629 AC: 6557 AN: 10418

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.604 AC: 40867 AN: 67710

Other (OTH) AF: 0.493 AC: 1033 AN: 2096

Alfa AF: 0.544 Hom.: 2842

Bravo AF: 0.457

Asia WGS AF: 0.392 AC: 1358 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism (auto)

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: rs45625639;

hg19: chr4-102091331;