4-101025791-T-C

Position:

• chr4-101025791-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000944.5(PPP3CA):​c.*74A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0926 in 1,221,396 control chromosomes in the GnomAD database, including 7,748 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2182 hom., cov: 22)
  • Exomes 𝑓: 0.085 (5566 hom.)
• Consequence: PPP3CA NM_000944.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.360

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 4-101025791-T-C is Benign according to our data. Variant chr4-101025791-T-C is described in ClinVar as [Benign]. Clinvar id is 1247668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP3CA	NM_000944.5	c.*74A>G		3_prime_UTR_variant	14/14	ENST00000394854.8	NP_000935.1
PPP3CA	NM_001130691.2	c.*74A>G		3_prime_UTR_variant	13/13		NP_001124163.1
PPP3CA	NM_001130692.2	c.*74A>G		3_prime_UTR_variant	12/12		NP_001124164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP3CA	ENST00000394854.8	c.*74A>G		3_prime_UTR_variant	14/14	1	NM_000944.5	ENSP00000378323	P3

Frequencies

GnomAD3 genomes AF: 0.161 AC: 20291 AN: 125700 Hom.: 2182 Cov.: 22

Gnomad AFR AF: 0.336

Gnomad AMI AF: 0.00339

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.0780

Gnomad OTH AF: 0.146

GnomAD4 exome AF: 0.0847 AC: 92813 AN: 1095632 Hom.: 5566 Cov.: 14 AF XY: 0.0873 AC XY: 47570 AN XY: 545150

Gnomad4 AFR exome AF: 0.300

Gnomad4 AMR exome AF: 0.0539

Gnomad4 ASJ exome AF: 0.114

Gnomad4 EAS exome AF: 0.145

Gnomad4 SAS exome AF: 0.189

Gnomad4 FIN exome AF: 0.0985

Gnomad4 NFE exome AF: 0.0678

Gnomad4 OTH exome AF: 0.0993

GnomAD4 genome AF: 0.162 AC: 20311 AN: 125764 Hom.: 2182 Cov.: 22 AF XY: 0.170 AC XY: 9914 AN XY: 58192

Gnomad4 AFR AF: 0.336

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.132

Gnomad4 EAS AF: 0.133

Gnomad4 SAS AF: 0.216

Gnomad4 FIN AF: 0.163

Gnomad4 NFE AF: 0.0780

Gnomad4 OTH AF: 0.153

Alfa AF: 0.0910 Hom.: 920

Bravo AF: 0.147

Asia WGS AF: 0.213 AC: 742 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.2
DANN	Benign	0.71

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: rs1042094; hg19: chr4-101946948;