rs7840

Variant names:

• chr4-101023512-T-A
• rs7840
• NM_000944.5:c.*2353A>T

Your query was ambiguous. Multiple possible variants found:

• chr4-101023512-T-A
• chr4-101023512-T-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000944.5(PPP3CA):​c.*2353A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 152,006 control chromosomes in the GnomAD database, including 2,087 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (2087 hom., cov: 32)
  • Exomes 𝑓: 0.083 (0 hom.)
• Consequence: PPP3CA NM_000944.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.179
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP3CA	NM_000944.5	c.*2353A>T		3_prime_UTR_variant	Exon 14 of 14	ENST00000394854.8	NP_000935.1
PPP3CA	NM_001130691.2	c.*2353A>T		3_prime_UTR_variant	Exon 13 of 13		NP_001124163.1
PPP3CA	NM_001130692.2	c.*2353A>T		3_prime_UTR_variant	Exon 12 of 12		NP_001124164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP3CA	ENST00000394854.8	c.*2353A>T		3_prime_UTR_variant	Exon 14 of 14	1	NM_000944.5	ENSP00000378323.3
PPP3CA	ENST00000323055.10	c.*2353A>T		3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000320580.6
PPP3CA	ENST00000512215.5	c.*2353A>T		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000422781.1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23909 AN: 151876 Hom.: 2089 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.0152

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.178

GnomAD4 exome AF: 0.0833 AC: 1 AN: 12 Hom.: 0 Cov.: 0 AF XY: 0.167 AC XY: 1 AN XY: 6

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0833 AC: 1 AN: 12

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.157 AC: 23906 AN: 151994 Hom.: 2087 Cov.: 32 AF XY: 0.153 AC XY: 11400 AN XY: 74286

African (AFR) AF: 0.106 AC: 4385 AN: 41482

American (AMR) AF: 0.149 AC: 2275 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 595 AN: 3466

East Asian (EAS) AF: 0.0154 AC: 80 AN: 5180

South Asian (SAS) AF: 0.187 AC: 901 AN: 4806

European-Finnish (FIN) AF: 0.142 AC: 1497 AN: 10556

Middle Eastern (MID) AF: 0.216 AC: 63 AN: 292

European-Non Finnish (NFE) AF: 0.199 AC: 13521 AN: 67946

Other (OTH) AF: 0.178 AC: 375 AN: 2108

Alfa AF: 0.0842 Hom.: 109

Bravo AF: 0.155

Asia WGS AF: 0.107 AC: 373 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.6
DANN	Benign	0.77
PhyloP100		-0.18
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: rs7840; hg19: chr4-101944669;