chr4-101025820-CAAAA-C

Variant names:

• chr4-101025820-CAAAA-C
• rs35434632
• NM_000944.5:c.*41_*44delTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000944.5(PPP3CA):​c.*41_*44delTTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0365 in 439,570 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.036 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PPP3CA NM_000944.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.*41_*44delTTTT		3_prime_UTR	Exon 14 of 14	NP_000935.1	Q08209-1
	PPP3CA	NM_001130691.2		c.*41_*44delTTTT		3_prime_UTR	Exon 13 of 13	NP_001124163.1	Q08209-2
	PPP3CA	NM_001130692.2		c.*41_*44delTTTT		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.*41_*44delTTTT		3_prime_UTR	Exon 14 of 14	ENSP00000378323.3	Q08209-1
	PPP3CA	ENST00000394853.8	TSL:1	c.*41_*44delTTTT		3_prime_UTR	Exon 13 of 13	ENSP00000378322.4	Q08209-2
	PPP3CA	ENST00000323055.10	TSL:1	c.*41_*44delTTTT		3_prime_UTR	Exon 12 of 12	ENSP00000320580.6	Q08209-3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 34564 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0217 AC: 924 AN: 42522 AF XY: 0.0220

Gnomad AFR exome AF: 0.0220

Gnomad AMR exome AF: 0.0490

Gnomad ASJ exome AF: 0.0260

Gnomad EAS exome AF: 0.0416

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.0156

Gnomad OTH exome AF: 0.0254

GnomAD4 exome AF: 0.0365 AC: 16029 AN: 439570 Hom.: 0 AF XY: 0.0363 AC XY: 8265 AN XY: 227514

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

African (AFR) AF: 0.0387 AC: 399 AN: 10316

American (AMR) AF: 0.0271 AC: 435 AN: 16060

Ashkenazi Jewish (ASJ) AF: 0.0391 AC: 285 AN: 7284

East Asian (EAS) AF: 0.0269 AC: 401 AN: 14914

South Asian (SAS) AF: 0.0432 AC: 1489 AN: 34444

European-Finnish (FIN) AF: 0.0338 AC: 791 AN: 23392

Middle Eastern (MID) AF: 0.0414 AC: 63 AN: 1522

European-Non Finnish (NFE) AF: 0.0366 AC: 11501 AN: 314356

Other (OTH) AF: 0.0385 AC: 665 AN: 17282

⚠️ 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: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 34600 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 15224

African (AFR) AF: 0.00 AC: 0 AN: 7966

American (AMR) AF: 0.00 AC: 0 AN: 1876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1164

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

South Asian (SAS) AF: 0.00 AC: 0 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

Alfa AF: 0.000122 Hom.: 53

ClinVar

Not reported in ClinVar

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;