4-101032165-C-T

Variant names:

• chr4-101032165-C-T
• rs2851060
• NM_000944.5:c.1339+102G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000944.5(PPP3CA):​c.1339+102G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.734 in 887,348 control chromosomes in the GnomAD database, including 246,529 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (44786 hom., cov: 32)
  • Exomes 𝑓: 0.73 (201743 hom.)
• Consequence: PPP3CA NM_000944.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.335
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 4-101032165-C-T is Benign according to our data. Variant chr4-101032165-C-T is described in ClinVar as Benign. ClinVar VariationId is 1243916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.872 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP3CA	NM_000944.5	c.1339+102G>A		intron_variant	Intron 12 of 13	ENST00000394854.8	NP_000935.1
PPP3CA	NM_001130691.2	c.1339+102G>A		intron_variant	Intron 12 of 12		NP_001124163.1
PPP3CA	NM_001130692.2	c.1213+102G>A		intron_variant	Intron 11 of 11		NP_001124164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP3CA	ENST00000394854.8	c.1339+102G>A		intron_variant	Intron 12 of 13	1	NM_000944.5	ENSP00000378323.3

Frequencies

GnomAD3 genomes AF: 0.753 AC: 114449 AN: 152034 Hom.: 44739 Cov.: 32

Gnomad AFR AF: 0.879

Gnomad AMI AF: 0.904

Gnomad AMR AF: 0.583

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.703

Gnomad FIN AF: 0.765

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.761

Gnomad OTH AF: 0.744

GnomAD4 exome AF: 0.730 AC: 536831 AN: 735196 Hom.: 201743 AF XY: 0.730 AC XY: 264853 AN XY: 362824

African (AFR) AF: 0.886 AC: 13570 AN: 15320

American (AMR) AF: 0.506 AC: 5965 AN: 11782

Ashkenazi Jewish (ASJ) AF: 0.723 AC: 9597 AN: 13276

East Asian (EAS) AF: 0.160 AC: 4261 AN: 26696

South Asian (SAS) AF: 0.710 AC: 20053 AN: 28236

European-Finnish (FIN) AF: 0.761 AC: 28790 AN: 37856

Middle Eastern (MID) AF: 0.772 AC: 3040 AN: 3938

European-Non Finnish (NFE) AF: 0.757 AC: 427921 AN: 565012

Other (OTH) AF: 0.714 AC: 23634 AN: 33080

GnomAD4 genome AF: 0.753 AC: 114540 AN: 152152 Hom.: 44786 Cov.: 32 AF XY: 0.744 AC XY: 55375 AN XY: 74384

African (AFR) AF: 0.879 AC: 36512 AN: 41530

American (AMR) AF: 0.582 AC: 8894 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2533 AN: 3472

East Asian (EAS) AF: 0.146 AC: 755 AN: 5160

South Asian (SAS) AF: 0.701 AC: 3373 AN: 4812

European-Finnish (FIN) AF: 0.765 AC: 8108 AN: 10600

Middle Eastern (MID) AF: 0.799 AC: 235 AN: 294

European-Non Finnish (NFE) AF: 0.761 AC: 51737 AN: 67976

Other (OTH) AF: 0.743 AC: 1570 AN: 2112

Alfa AF: 0.741 Hom.: 132299

Bravo AF: 0.739

Asia WGS AF: 0.481 AC: 1676 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 14, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.1
DANN	Benign	0.85
PhyloP100		-0.34
Mutation Taster		=100/0	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: rs2851060; hg19: chr4-101953322; COSMIC: COSV59932094;