rs1553920374

Variant names:

• chr4-101032267-C-A
• rs1553920374
• NM_000944.5:c.1339G>T

Your query was ambiguous. Multiple possible variants found:

• chr4-101032267-C-A
• chr4-101032267-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_000944.5(PPP3CA):​c.1339G>T​(p.Ala447Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A447T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PPP3CA NM_000944.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.62
• Publications: 0 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-101032267-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 441273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP3CA	NM_000944.5	c.1339G>T	p.Ala447Ser	missense_variant, splice_region_variant	Exon 12 of 14	ENST00000394854.8	NP_000935.1
PPP3CA	NM_001130691.2	c.1339G>T	p.Ala447Ser	missense_variant, splice_region_variant	Exon 12 of 13		NP_001124163.1
PPP3CA	NM_001130692.2	c.1213G>T	p.Ala405Ser	missense_variant, splice_region_variant	Exon 11 of 12		NP_001124164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP3CA	ENST00000394854.8	c.1339G>T	p.Ala447Ser	missense_variant, splice_region_variant	Exon 12 of 14	1	NM_000944.5	ENSP00000378323.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443144 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 717108

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32592

American (AMR) AF: 0.0000241 AC: 1 AN: 41426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25216

East Asian (EAS) AF: 0.00 AC: 0 AN: 38936

South Asian (SAS) AF: 0.00 AC: 0 AN: 82900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103880

Other (OTH) AF: 0.00 AC: 0 AN: 59542

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	.;T;.;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.33	T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.8	.;M;.;M;.
PhyloP100		7.6
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.1	N;N;N;N;N
REVEL	Benign	0.26
Sift	Uncertain	0.0060	D;T;D;D;T
Sift4G	Uncertain	0.034	D;T;T;T;T
Polyphen		0.99, 0.043	.;D;.;B;.
Vest4		0.59
MutPred		0.40		.;Gain of disorder (P = 0.0309);.;Gain of disorder (P = 0.0309);.;
MVP		0.52
MPC		1.5
ClinPred		0.95	D
GERP RS		5.4
Varity_R		0.22
gMVP		0.74
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
Splicevardb		3.0
SpliceAI score (max)		0.60		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.60		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553920374; hg19: chr4-101953424; COSMIC: COSV100547524;