Genetic Variant ENSG00000254531:n.51T>C (chr4-101347783-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000527564.3(ENSG00000254531):n.51T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.435 in 155,222 control chromosomes in the GnomAD database, including 17,278 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 0.44 ( 17112 hom., cov: 34)

Exomes 𝑓: 0.30 ( 166 hom. )

Consequence

ENSG00000254531
ENST00000527564.3 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.42

Publications

9 publications found

Variant links:

Genes affected

ENSG00000254531 (HGNC:58118):

ENSG00000254531 links:

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

PPP3CA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP3CA-DT	NR_033874.1 link	n.7T>C		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
ENSG00000254531	ENST00000527564.3 link	n.51T>C	non_coding_transcript_exon_variant	Exon 1 of 2	2
ENSG00000254531	ENST00000529296.4 link	n.38T>C	non_coding_transcript_exon_variant	Exon 1 of 2	5
ENSG00000254531	ENST00000689482.2 link	n.8T>C	non_coding_transcript_exon_variant	Exon 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.438

AC:

66540

AN:

152018

Hom.:

17065

Cov.:

show subpopulations

Gnomad AFR

AF:

0.703

Gnomad AMI

AF:

0.401

Gnomad AMR

AF:

0.441

Gnomad ASJ

AF:

0.276

Gnomad EAS

AF:

0.524

Gnomad SAS

AF:

0.414

Gnomad FIN

AF:

0.425

Gnomad MID

AF:

0.212

Gnomad NFE

AF:

0.284

Gnomad OTH

AF:

0.379

GnomAD4 exome

AF:

0.304

AC:

937

AN:

3086

Hom.:

166

Cov.:

AF XY:

0.318

AC XY:

638

AN XY:

2008

show subpopulations

African (AFR)

AF:

0.789

AC:

AN:

American (AMR)

AF:

0.367

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.208

AC:

AN:

East Asian (EAS)

AF:

0.362

AC:

AN:

South Asian (SAS)

AF:

0.350

AC:

131

AN:

374

European-Finnish (FIN)

AF:

0.429

AC:

AN:

Middle Eastern (MID)

AF:

0.143

AC:

AN:

European-Non Finnish (NFE)

AF:

0.279

AC:

649

AN:

2326

Other (OTH)

AF:

0.386

AC:

AN:

166

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

111

139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.438

AC:

66650

AN:

152136

Hom.:

17112

Cov.:

AF XY:

0.445

AC XY:

33103

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.704

AC:

29201

AN:

41508

American (AMR)

AF:

0.441

AC:

6746

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.276

AC:

956

AN:

3468

East Asian (EAS)

AF:

0.524

AC:

2699

AN:

5154

South Asian (SAS)

AF:

0.413

AC:

1991

AN:

4820

European-Finnish (FIN)

AF:

0.425

AC:

4493

AN:

10574

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.284

AC:

19321

AN:

68010

Other (OTH)

AF:

0.385

AC:

814

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1778

3556

5335

7113

8891

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

570

1140

1710

2280

2850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.302

Hom.:

1382

Bravo

AF:

0.453

Asia WGS

AF:

0.520

AC:

1809

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

6.3

(source)

DANN

Benign

0.81

PhyloP100

-1.4

PromoterAI

-0.014

Neutral

(source)

Mutation Taster

=298/2

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over