4-101025820-CAAAAAAAAAAAAAAAAAA-CAAAAAAAAAAAAAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000944.5(PPP3CA):​c.*44delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.40 (292 hom., cov: 0)
  • Exomes 𝑓: 0.11 (224 hom.)
  • Failed GnomAD Quality Control
• Consequence: PPP3CA NM_000944.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 4-101025820-CA-C is Benign according to our data. Variant chr4-101025820-CA-C is described in ClinVar as Benign. ClinVar VariationId is 1289310.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 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.*44delT		3_prime_UTR	Exon 14 of 14	NP_000935.1	Q08209-1
	PPP3CA	NM_001130691.2		c.*44delT		3_prime_UTR	Exon 13 of 13	NP_001124163.1	Q08209-2
	PPP3CA	NM_001130692.2		c.*44delT		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.*44delT		3_prime_UTR	Exon 14 of 14	ENSP00000378323.3	Q08209-1
	PPP3CA	ENST00000394853.8	TSL:1	c.*44delT		3_prime_UTR	Exon 13 of 13	ENSP00000378322.4	Q08209-2
	PPP3CA	ENST00000323055.10	TSL:1	c.*44delT		3_prime_UTR	Exon 12 of 12	ENSP00000320580.6	Q08209-3

Frequencies

GnomAD3 genomes AF: 0.400 AC: 13788 AN: 34454 Hom.: 292 Cov.: 0

Gnomad AFR AF: 0.362

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.0385

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.400

Gnomad NFE AF: 0.430

Gnomad OTH AF: 0.388

GnomAD2 exomes AF: 0.0241 AC: 1024 AN: 42522 AF XY: 0.0244

Gnomad AFR exome AF: 0.0246

Gnomad AMR exome AF: 0.0574

Gnomad ASJ exome AF: 0.0375

Gnomad EAS exome AF: 0.0502

Gnomad FIN exome AF: 0.00369

Gnomad NFE exome AF: 0.0149

Gnomad OTH exome AF: 0.0344

GnomAD4 exome AF: 0.106 AC: 47001 AN: 441748 Hom.: 224 Cov.: 0 AF XY: 0.103 AC XY: 23616 AN XY: 228732

African (AFR) AF: 0.0912 AC: 945 AN: 10364

American (AMR) AF: 0.0372 AC: 600 AN: 16150

Ashkenazi Jewish (ASJ) AF: 0.0934 AC: 684 AN: 7320

East Asian (EAS) AF: 0.0633 AC: 953 AN: 15046

South Asian (SAS) AF: 0.0596 AC: 2068 AN: 34682

European-Finnish (FIN) AF: 0.0743 AC: 1745 AN: 23480

Middle Eastern (MID) AF: 0.0909 AC: 138 AN: 1518

European-Non Finnish (NFE) AF: 0.120 AC: 38025 AN: 315800

Other (OTH) AF: 0.106 AC: 1843 AN: 17388

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.400 AC: 13791 AN: 34490 Hom.: 292 Cov.: 0 AF XY: 0.387 AC XY: 5874 AN XY: 15174

African (AFR) AF: 0.361 AC: 2877 AN: 7966

American (AMR) AF: 0.369 AC: 689 AN: 1868

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 473 AN: 1154

East Asian (EAS) AF: 0.0381 AC: 17 AN: 446

South Asian (SAS) AF: 0.208 AC: 113 AN: 542

European-Finnish (FIN) AF: 0.253 AC: 87 AN: 344

Middle Eastern (MID) AF: 0.400 AC: 12 AN: 30

European-Non Finnish (NFE) AF: 0.430 AC: 9185 AN: 21350

Other (OTH) AF: 0.386 AC: 153 AN: 396

Alfa AF: 0.0724 Hom.: 53

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs35434632; hg19: chr4-101946977;