NM_000944.5:c.59-30372C>G

Variant names:

• chr4-101226488-G-C
• rs713455
• NM_000944.5:c.59-30372C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000944.5(PPP3CA):​c.59-30372C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.663 in 151,508 control chromosomes in the GnomAD database, including 34,283 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.66 (34283 hom., cov: 31)
• Consequence: PPP3CA NM_000944.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.143
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP3CA	NM_000944.5	c.59-30372C>G		intron_variant	Intron 1 of 13	ENST00000394854.8	NP_000935.1
PPP3CA	NM_001130691.2	c.59-30372C>G		intron_variant	Intron 1 of 12		NP_001124163.1
PPP3CA	NM_001130692.2	c.59-30372C>G		intron_variant	Intron 1 of 11		NP_001124164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP3CA	ENST00000394854.8	c.59-30372C>G		intron_variant	Intron 1 of 13	1	NM_000944.5	ENSP00000378323.3

Frequencies

GnomAD3 genomes AF: 0.663 AC: 100414 AN: 151388 Hom.: 34275 Cov.: 31

Gnomad AFR AF: 0.604

Gnomad AMI AF: 0.825

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.604

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.547

Gnomad FIN AF: 0.778

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.744

Gnomad OTH AF: 0.658

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

GnomAD4 genome AF: 0.663 AC: 100450 AN: 151508 Hom.: 34283 Cov.: 31 AF XY: 0.657 AC XY: 48653 AN XY: 74016

African (AFR) AF: 0.604 AC: 24959 AN: 41342

American (AMR) AF: 0.544 AC: 8259 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 2089 AN: 3458

East Asian (EAS) AF: 0.307 AC: 1569 AN: 5114

South Asian (SAS) AF: 0.546 AC: 2632 AN: 4820

European-Finnish (FIN) AF: 0.778 AC: 8231 AN: 10576

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.744 AC: 50373 AN: 67714

Other (OTH) AF: 0.652 AC: 1371 AN: 2104

Alfa AF: 0.615 Hom.: 1890

Bravo AF: 0.638

Asia WGS AF: 0.439 AC: 1528 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.80
DANN	Benign	0.36
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs713455; hg19: chr4-102147645;