4-101025820-CAAAAAAAAAAAAAAAAAA-CAAAAAAAAAAAAAAAA

Variant names:

• chr4-101025820-CAA-C
• rs35434632
• NM_000944.5:c.*43_*44delTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_000944.5(PPP3CA):​c.*43_*44delTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.08 in 440,692 control chromosomes in the GnomAD database, including 11 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.025 (5 hom., cov: 0)
  • Exomes 𝑓: 0.080 (11 hom.)
  • Failed GnomAD Quality Control
• Consequence: PPP3CA NM_000944.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.56
• Publications: 1 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_benign. The variant received -2 ACMG points.

• BP6: Variant 4-101025820-CAA-C is Benign according to our data. Variant chr4-101025820-CAA-C is described in ClinVar as Benign. ClinVar VariationId is 1273530.Status of the report is criteria_provided_single_submitter, 1 stars.

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.*43_*44delTT		3_prime_UTR	Exon 14 of 14	NP_000935.1	Q08209-1
	PPP3CA	NM_001130691.2		c.*43_*44delTT		3_prime_UTR	Exon 13 of 13	NP_001124163.1	Q08209-2
	PPP3CA	NM_001130692.2		c.*43_*44delTT		3_prime_UTR	Exon 12 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.*43_*44delTT		3_prime_UTR	Exon 14 of 14	ENSP00000378323.3	Q08209-1
	PPP3CA	ENST00000394853.8	TSL:1	c.*43_*44delTT		3_prime_UTR	Exon 13 of 13	ENSP00000378322.4	Q08209-2
	PPP3CA	ENST00000323055.10	TSL:1	c.*43_*44delTT		3_prime_UTR	Exon 12 of 12	ENSP00000320580.6	Q08209-3

Frequencies

GnomAD3 genomes AF: 0.0248 AC: 856 AN: 34480 Hom.: 5 Cov.: 0

Gnomad AFR AF: 0.0727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0209

Gnomad ASJ AF: 0.00172

Gnomad EAS AF: 0.00905

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.00585

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00715

Gnomad OTH AF: 0.0325

GnomAD2 exomes AF: 0.0315 AC: 1338 AN: 42522 AF XY: 0.0307

Gnomad AFR exome AF: 0.0338

Gnomad AMR exome AF: 0.0565

Gnomad ASJ exome AF: 0.0466

Gnomad EAS exome AF: 0.0607

Gnomad FIN exome AF: 0.00604

Gnomad NFE exome AF: 0.0224

Gnomad OTH exome AF: 0.0543

GnomAD4 exome AF: 0.0800 AC: 35238 AN: 440692 Hom.: 11 AF XY: 0.0783 AC XY: 17857 AN XY: 228142

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

African (AFR) AF: 0.0747 AC: 772 AN: 10338

American (AMR) AF: 0.0404 AC: 651 AN: 16114

Ashkenazi Jewish (ASJ) AF: 0.0810 AC: 591 AN: 7296

East Asian (EAS) AF: 0.0644 AC: 962 AN: 14938

South Asian (SAS) AF: 0.0666 AC: 2302 AN: 34560

European-Finnish (FIN) AF: 0.0605 AC: 1421 AN: 23484

Middle Eastern (MID) AF: 0.0647 AC: 99 AN: 1530

European-Non Finnish (NFE) AF: 0.0857 AC: 27002 AN: 315028

Other (OTH) AF: 0.0826 AC: 1438 AN: 17404

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0248 AC: 857 AN: 34516 Hom.: 5 Cov.: 0 AF XY: 0.0262 AC XY: 397 AN XY: 15170

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

African (AFR) AF: 0.0727 AC: 576 AN: 7924

American (AMR) AF: 0.0208 AC: 39 AN: 1872

Ashkenazi Jewish (ASJ) AF: 0.00172 AC: 2 AN: 1160

East Asian (EAS) AF: 0.00897 AC: 4 AN: 446

South Asian (SAS) AF: 0.128 AC: 68 AN: 532

European-Finnish (FIN) AF: 0.00585 AC: 2 AN: 342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 30

European-Non Finnish (NFE) AF: 0.00714 AC: 153 AN: 21414

Other (OTH) AF: 0.0323 AC: 13 AN: 402

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00343 Hom.: 53

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism

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: rs35434632; hg19: chr4-101946977;