Genetic Variant NM_000944.5:c.*8C>T (chr4-101025857-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000944.5(PPP3CA):c.*8C>T variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.00132 in 1,109,424 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0053 ( 6 hom., cov: 29)

Exomes 𝑓: 0.00071 ( 5 hom. )

Consequence

PPP3CA
NM_000944.5 3_prime_UTR

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 4.56

Publications

0 publications found

Variant links:

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

PPP3CA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 4-101025857-G-A is Benign according to our data. Variant chr4-101025857-G-A is described in ClinVar as Benign. ClinVar VariationId is 3044125.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00533 (779/146150) while in subpopulation AFR AF = 0.0185 (733/39640). AF 95% confidence interval is 0.0174. There are 6 homozygotes in GnomAd4. There are 365 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High AC in GnomAd4 at 779 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PPP3CA	NM_000944.5	MANE Select	c.*8C>T	3_prime_UTR	Exon 14 of 14	NP_000935.1	Q08209-1
PPP3CA	NM_001130691.2		c.*8C>T	3_prime_UTR	Exon 13 of 13	NP_001124163.1	Q08209-2
PPP3CA	NM_001130692.2		c.*8C>T	3_prime_UTR	Exon 12 of 12	NP_001124164.1	Q08209-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PPP3CA	ENST00000394854.8	TSL:1 MANE Select	c.*8C>T	3_prime_UTR	Exon 14 of 14	ENSP00000378323.3	Q08209-1
PPP3CA	ENST00000394853.8	TSL:1	c.*8C>T	3_prime_UTR	Exon 13 of 13	ENSP00000378322.4	Q08209-2
PPP3CA	ENST00000323055.10	TSL:1	c.*8C>T	3_prime_UTR	Exon 12 of 12	ENSP00000320580.6	Q08209-3

Frequencies

GnomAD3 genomes

AF:

0.00532

AC:

777

AN:

146082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0185

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00179

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000225

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000165

Gnomad OTH

AF:

0.00402

GnomAD2 exomes

AF:

0.00168

AC:

313

AN:

186662

AF XY:

0.00112

show subpopulations

Gnomad AFR exome

AF:

0.0200

Gnomad AMR exome

AF:

0.00106

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.000246

GnomAD4 exome

AF:

0.000706

AC:

680

AN:

963274

Hom.:

Cov.:

AF XY:

0.000605

AC XY:

292

AN XY:

483036

show subpopulations

African (AFR)

AF:

0.0240

AC:

497

AN:

20732

American (AMR)

AF:

0.00124

AC:

AN:

24252

Ashkenazi Jewish (ASJ)

AF:

0.0000605

AC:

AN:

16530

East Asian (EAS)

AF:

0.0000393

AC:

AN:

25434

South Asian (SAS)

AF:

0.0000683

AC:

AN:

58582

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45322

Middle Eastern (MID)

AF:

0.000517

AC:

AN:

3866

European-Non Finnish (NFE)

AF:

0.000110

AC:

AN:

729248

Other (OTH)

AF:

0.00165

AC:

AN:

39308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

114

142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00533

AC:

779

AN:

146150

Hom.:

Cov.:

AF XY:

0.00515

AC XY:

365

AN XY:

70902

show subpopulations

African (AFR)

AF:

0.0185

AC:

733

AN:

39640

American (AMR)

AF:

0.00179

AC:

AN:

14532

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3432

East Asian (EAS)

AF:

0.00

AC:

AN:

5000

South Asian (SAS)

AF:

0.000226

AC:

AN:

4424

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9176

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.000165

AC:

AN:

66768

Other (OTH)

AF:

0.00399

AC:

AN:

2006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

124

165

206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00326

Hom.:

Bravo

AF:

0.00648

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

PPP3CA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.76

PhyloP100

4.6

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over