4-101195926-C-T

Variant names:

• chr4-101195926-C-T
• rs3730251
• NM_000944.5:c.249G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000944.5(PPP3CA):​c.249G>A​(p.Ala83Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,613,482 control chromosomes in the GnomAD database, including 1,755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A83A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.062 (953 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (802 hom.)
• Consequence: PPP3CA NM_000944.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.05
• Publications: 7 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 4-101195926-C-T is Benign according to our data. Variant chr4-101195926-C-T is described in ClinVar as Benign. ClinVar VariationId is 1290046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.202 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.249G>A	p.Ala83Ala	synonymous	Exon 2 of 14	NP_000935.1	Q08209-1
	PPP3CA	NM_001130691.2		c.249G>A	p.Ala83Ala	synonymous	Exon 2 of 13	NP_001124163.1	Q08209-2
	PPP3CA	NM_001130692.2		c.249G>A	p.Ala83Ala	synonymous	Exon 2 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.249G>A	p.Ala83Ala	synonymous	Exon 2 of 14	ENSP00000378323.3	Q08209-1
	PPP3CA	ENST00000394853.8	TSL:1	c.249G>A	p.Ala83Ala	synonymous	Exon 2 of 13	ENSP00000378322.4	Q08209-2
	PPP3CA	ENST00000323055.10	TSL:1	c.249G>A	p.Ala83Ala	synonymous	Exon 2 of 12	ENSP00000320580.6	Q08209-3

Frequencies

GnomAD3 genomes AF: 0.0619 AC: 9414 AN: 152046 Hom.: 951 Cov.: 32

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0284

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0351

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.0407

GnomAD2 exomes AF: 0.0211 AC: 5297 AN: 250614 AF XY: 0.0169

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.0142

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.0436

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00215

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.00858 AC: 12545 AN: 1461318 Hom.: 802 Cov.: 31 AF XY: 0.00794 AC XY: 5769 AN XY: 726942

African (AFR) AF: 0.206 AC: 6904 AN: 33446

American (AMR) AF: 0.0160 AC: 715 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.000997 AC: 26 AN: 26086

East Asian (EAS) AF: 0.0239 AC: 947 AN: 39684

South Asian (SAS) AF: 0.00809 AC: 697 AN: 86186

European-Finnish (FIN) AF: 0.0000750 AC: 4 AN: 53360

Middle Eastern (MID) AF: 0.0224 AC: 129 AN: 5762

European-Non Finnish (NFE) AF: 0.00181 AC: 2014 AN: 1111730

Other (OTH) AF: 0.0184 AC: 1109 AN: 60366

GnomAD4 genome AF: 0.0620 AC: 9440 AN: 152164 Hom.: 953 Cov.: 32 AF XY: 0.0595 AC XY: 4424 AN XY: 74394

African (AFR) AF: 0.205 AC: 8518 AN: 41464

American (AMR) AF: 0.0283 AC: 432 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3466

East Asian (EAS) AF: 0.0352 AC: 182 AN: 5176

South Asian (SAS) AF: 0.0139 AC: 67 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00215 AC: 146 AN: 68020

Other (OTH) AF: 0.0402 AC: 85 AN: 2112

Alfa AF: 0.0247 Hom.: 213

Bravo AF: 0.0712

Asia WGS AF: 0.0300 AC: 104 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00303

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.7
DANN	Benign	0.60
PhyloP100		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3730251; hg19: chr4-102117083;