4-101025857-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000944.5(PPP3CA):c.*8C>T variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.00132 in 1,109,424 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0053 (6 hom., cov: 29)
  • Exomes 𝑓: 0.00071 (5 hom.)
• Consequence: PPP3CA NM_000944.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.56

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 4-101025857-G-A is Benign according to our data. Variant chr4-101025857-G-A is described in ClinVar as [Benign]. Clinvar id is 3044125.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00533 (779/146150) while in subpopulation AFR AF= 0.0185 (733/39640). AF 95% confidence interval is 0.0174. There are 6 homozygotes in gnomad4. There are 365 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High AC in GnomAd at 777 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP3CA	NM_000944.5	c.*8C>T		3_prime_UTR_variant	14/14	ENST00000394854.8
PPP3CA	NM_001130691.2	c.*8C>T		3_prime_UTR_variant	13/13
PPP3CA	NM_001130692.2	c.*8C>T		3_prime_UTR_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP3CA	ENST00000394854.8	c.*8C>T		3_prime_UTR_variant	14/14	1	NM_000944.5	P3

Frequencies

GnomAD3 genomes AF: 0.00532 AC: 777 AN: 146082 Hom.: 6 Cov.: 29

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00179

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000225

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000165

Gnomad OTH AF: 0.00402

GnomAD3 exomes AF: 0.00168 AC: 313 AN: 186662 Hom.: 1 AF XY: 0.00112 AC XY: 115 AN XY: 102472

Gnomad AFR exome AF: 0.0200

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000246

GnomAD4 exome AF: 0.000706 AC: 680 AN: 963274 Hom.: 5 Cov.: 26 AF XY: 0.000605 AC XY: 292 AN XY: 483036

Gnomad4 AFR exome AF: 0.0240

Gnomad4 AMR exome AF: 0.00124

Gnomad4 ASJ exome AF: 0.0000605

Gnomad4 EAS exome AF: 0.0000393

Gnomad4 SAS exome AF: 0.0000683

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.00165

GnomAD4 genome AF: 0.00533 AC: 779 AN: 146150 Hom.: 6 Cov.: 29 AF XY: 0.00515 AC XY: 365 AN XY: 70902

Gnomad4 AFR AF: 0.0185

Gnomad4 AMR AF: 0.00179

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000226

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000165

Gnomad4 OTH AF: 0.00399

Alfa AF: 0.00326 Hom.: 4

Bravo AF: 0.00648

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PPP3CA-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	16
Dann	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs112303474; hg19: chr4-101947014;