rs3804357

Variant names:

• chr4-101080966-C-A
• rs3804357
• NM_000944.5:c.861-340G>T

Your query was ambiguous. Multiple possible variants found:

• chr4-101080966-C-A
• chr4-101080966-C-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.861-340G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 151,726 control chromosomes in the GnomAD database, including 7,203 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 0.30 (7203 hom., cov: 31)
• Consequence: PPP3CA NM_000944.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.919
• Publications: 9 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP3CA	NM_000944.5	c.861-340G>T		intron_variant	Intron 7 of 13	ENST00000394854.8	NP_000935.1
PPP3CA	NM_001130691.2	c.861-340G>T		intron_variant	Intron 7 of 12		NP_001124163.1
PPP3CA	NM_001130692.2	c.861-340G>T		intron_variant	Intron 7 of 11		NP_001124164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP3CA	ENST00000394854.8	c.861-340G>T		intron_variant	Intron 7 of 13	1	NM_000944.5	ENSP00000378323.3

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45419 AN: 151608 Hom.: 7195 Cov.: 31

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.365

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.318

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

GnomAD4 genome AF: 0.299 AC: 45438 AN: 151726 Hom.: 7203 Cov.: 31 AF XY: 0.294 AC XY: 21779 AN XY: 74140

African (AFR) AF: 0.286 AC: 11851 AN: 41392

American (AMR) AF: 0.247 AC: 3768 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 1420 AN: 3462

East Asian (EAS) AF: 0.216 AC: 1118 AN: 5172

South Asian (SAS) AF: 0.486 AC: 2343 AN: 4818

European-Finnish (FIN) AF: 0.183 AC: 1930 AN: 10536

Middle Eastern (MID) AF: 0.362 AC: 105 AN: 290

European-Non Finnish (NFE) AF: 0.324 AC: 21959 AN: 67806

Other (OTH) AF: 0.325 AC: 684 AN: 2104

Alfa AF: 0.319 Hom.: 30126

Bravo AF: 0.302

Asia WGS AF: 0.388 AC: 1345 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.89
DANN	Benign	0.29
PhyloP100		-0.92
Mutation Taster		=97/3	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: rs3804357; hg19: chr4-102002123;