4-101025820-CAAA-C

Variant names:

• chr4-101025820-CAAA-C
• rs35434632
• NM_000944.5:c.*42_*44delTTT

Variant summary

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

The NM_000944.5(PPP3CA):​c.*42_*44delTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0638 in 438,870 control chromosomes in the GnomAD database, including 6 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 0.00058 (0 hom., cov: 0)
  • Exomes 𝑓: 0.064 (6 hom.)
  • Failed GnomAD Quality Control
• Consequence: PPP3CA NM_000944.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.74
• 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-CAAA-C is Benign according to our data. Variant chr4-101025820-CAAA-C is described in ClinVar as Benign. ClinVar VariationId is 1229591.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.*42_*44delTTT		3_prime_UTR	Exon 14 of 14	NP_000935.1	Q08209-1
	PPP3CA	NM_001130691.2		c.*42_*44delTTT		3_prime_UTR	Exon 13 of 13	NP_001124163.1	Q08209-2
	PPP3CA	NM_001130692.2		c.*42_*44delTTT		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.*42_*44delTTT		3_prime_UTR	Exon 14 of 14	ENSP00000378323.3	Q08209-1
	PPP3CA	ENST00000394853.8	TSL:1	c.*42_*44delTTT		3_prime_UTR	Exon 13 of 13	ENSP00000378322.4	Q08209-2
	PPP3CA	ENST00000323055.10	TSL:1	c.*42_*44delTTT		3_prime_UTR	Exon 12 of 12	ENSP00000320580.6	Q08209-3

Frequencies

GnomAD3 genomes AF: 0.000579 AC: 20 AN: 34560 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00214

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000535

Gnomad ASJ AF: 0.000859

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0340 AC: 1445 AN: 42522 AF XY: 0.0339

Gnomad AFR exome AF: 0.0321

Gnomad AMR exome AF: 0.0830

Gnomad ASJ exome AF: 0.0313

Gnomad EAS exome AF: 0.0572

Gnomad FIN exome AF: 0.00436

Gnomad NFE exome AF: 0.0251

Gnomad OTH exome AF: 0.0489

GnomAD4 exome AF: 0.0638 AC: 28012 AN: 438870 Hom.: 6 AF XY: 0.0636 AC XY: 14434 AN XY: 227096

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

African (AFR) AF: 0.0684 AC: 705 AN: 10304

American (AMR) AF: 0.0383 AC: 613 AN: 16008

Ashkenazi Jewish (ASJ) AF: 0.0639 AC: 466 AN: 7290

East Asian (EAS) AF: 0.0490 AC: 728 AN: 14868

South Asian (SAS) AF: 0.0668 AC: 2300 AN: 34428

European-Finnish (FIN) AF: 0.0506 AC: 1181 AN: 23356

Middle Eastern (MID) AF: 0.0550 AC: 84 AN: 1526

European-Non Finnish (NFE) AF: 0.0663 AC: 20822 AN: 313830

Other (OTH) AF: 0.0645 AC: 1113 AN: 17260

⚠️ 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: 0.000578 AC: 20 AN: 34596 Hom.: 0 Cov.: 0 AF XY: 0.000657 AC XY: 10 AN XY: 15224

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

African (AFR) AF: 0.00214 AC: 17 AN: 7962

American (AMR) AF: 0.000533 AC: 1 AN: 1876

Ashkenazi Jewish (ASJ) AF: 0.000859 AC: 1 AN: 1164

East Asian (EAS) AF: 0.00 AC: 0 AN: 446

South Asian (SAS) AF: 0.00185 AC: 1 AN: 540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 344

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 21440

Other (OTH) AF: 0.00 AC: 0 AN: 400

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000983093), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000490 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		1.7
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;