chr4-101025858-G-T

Variant names:

• chr4-101025858-G-T
• rs114065681
• NM_000944.5:c.*7C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000944.5(PPP3CA):​c.*7C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,058,810 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0083 (14 hom., cov: 29)
  • Exomes 𝑓: 0.012 (107 hom.)
• Consequence: PPP3CA NM_000944.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.69
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 4-101025858-G-T is Benign according to our data. Variant chr4-101025858-G-T is described in ClinVar as Benign. ClinVar VariationId is 1695101.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 1158 AD gene.

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.*7C>A		3_prime_UTR	Exon 14 of 14	NP_000935.1	Q08209-1
	PPP3CA	NM_001130691.2		c.*7C>A		3_prime_UTR	Exon 13 of 13	NP_001124163.1	Q08209-2
	PPP3CA	NM_001130692.2		c.*7C>A		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.*7C>A		3_prime_UTR	Exon 14 of 14	ENSP00000378323.3	Q08209-1
	PPP3CA	ENST00000394853.8	TSL:1	c.*7C>A		3_prime_UTR	Exon 13 of 13	ENSP00000378322.4	Q08209-2
	PPP3CA	ENST00000323055.10	TSL:1	c.*7C>A		3_prime_UTR	Exon 12 of 12	ENSP00000320580.6	Q08209-3

Frequencies

GnomAD3 genomes AF: 0.00829 AC: 1158 AN: 139742 Hom.: 14 Cov.: 29

Gnomad AFR AF: 0.00139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00557

Gnomad ASJ AF: 0.00118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00116

Gnomad FIN AF: 0.0478

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.0102 AC: 2017 AN: 198388 AF XY: 0.0100

Gnomad AFR exome AF: 0.00171

Gnomad AMR exome AF: 0.00280

Gnomad ASJ exome AF: 0.00148

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0455

Gnomad NFE exome AF: 0.0104

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.0120 AC: 11017 AN: 919020 Hom.: 107 Cov.: 26 AF XY: 0.0115 AC XY: 5360 AN XY: 464856

African (AFR) AF: 0.00168 AC: 33 AN: 19666

American (AMR) AF: 0.00339 AC: 89 AN: 26234

Ashkenazi Jewish (ASJ) AF: 0.00143 AC: 24 AN: 16780

East Asian (EAS) AF: 0.00 AC: 0 AN: 27200

South Asian (SAS) AF: 0.000929 AC: 59 AN: 63528

European-Finnish (FIN) AF: 0.0494 AC: 2256 AN: 45692

Middle Eastern (MID) AF: 0.00138 AC: 5 AN: 3622

European-Non Finnish (NFE) AF: 0.0121 AC: 8182 AN: 678146

Other (OTH) AF: 0.00967 AC: 369 AN: 38152

GnomAD4 genome AF: 0.00828 AC: 1158 AN: 139790 Hom.: 14 Cov.: 29 AF XY: 0.00920 AC XY: 618 AN XY: 67168

African (AFR) AF: 0.00139 AC: 52 AN: 37516

American (AMR) AF: 0.00557 AC: 78 AN: 14012

Ashkenazi Jewish (ASJ) AF: 0.00118 AC: 4 AN: 3378

East Asian (EAS) AF: 0.00 AC: 0 AN: 5000

South Asian (SAS) AF: 0.00116 AC: 5 AN: 4310

European-Finnish (FIN) AF: 0.0478 AC: 354 AN: 7404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 244

European-Non Finnish (NFE) AF: 0.0100 AC: 653 AN: 65094

Other (OTH) AF: 0.00617 AC: 12 AN: 1946

Alfa AF: 0.00876 Hom.: 19

Bravo AF: 0.00540

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Benign	0.77
PhyloP100		2.7
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: rs114065681; hg19: chr4-101947015;