Genetic Variant NM_002583.4:c.125C>T (chr12-79690120-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_002583.4(PAWR):c.125C>T(p.Pro42Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000815 in 1,486,592 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0044 ( 6 hom., cov: 31)

Exomes 𝑓: 0.00040 ( 2 hom. )

Consequence

PAWR
NM_002583.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.201

Publications

2 publications found

Variant links:

Genes affected

PAWR (HGNC:8614): (pro-apoptotic WT1 regulator) This gene encodes a tumor suppressor protein that selectively induces apoptosis in cancer cells through intracellular and extracellular mechanisms. The intracellular mechanism involves the inhibition of pro-survival pathways and the activation of Fas-mediated apoptosis, while the extracellular mechanism involves the binding of a secreted form of this protein to glucose regulated protein 78 (GRP78) on the cell surface, which leads to activation of the extrinsic apoptotic pathway. This gene is located on the unstable human chromosomal 12q21 region and is often deleted or mutated different tumors. The encoded protein also plays an important role in the progression of age-related diseases. [provided by RefSeq, Aug 2017]

PAWR links:

PPP1R12A-AS2 (HGNC:55456): (PPP1R12A antisense RNA 2)

PPP1R12A-AS2 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 (MetaRNN=0.0044992566).

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000402 (537/1335048) while in subpopulation AFR AF = 0.0163 (442/27124). AF 95% confidence interval is 0.015. There are 2 homozygotes in GnomAdExome4. There are 216 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 674 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAWR	NM_002583.4 link	c.125C>T	p.Pro42Leu	missense_variant	Exon 2 of 7	ENST00000328827.9	NP_002574.2	Q96IZ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAWR	ENST00000328827.9 link	c.125C>T	p.Pro42Leu	missense_variant	Exon 2 of 7	1	NM_002583.4	ENSP00000328088.4		Q96IZ0

Frequencies

GnomAD3 genomes

AF:

0.00444

AC:

672

AN:

151432

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0155

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00385

GnomAD2 exomes

AF:

0.000561

AC:

AN:

90954

AF XY:

0.000501

show subpopulations

Gnomad AFR exome

AF:

0.0189

Gnomad AMR exome

AF:

0.00103

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000233

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00111

GnomAD4 exome

AF:

0.000402

AC:

537

AN:

1335048

Hom.:

Cov.:

AF XY:

0.000328

AC XY:

216

AN XY:

659090

show subpopulations

African (AFR)

AF:

0.0163

AC:

442

AN:

27124

American (AMR)

AF:

0.00101

AC:

AN:

30676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23560

East Asian (EAS)

AF:

0.00

AC:

AN:

29908

South Asian (SAS)

AF:

0.0000132

AC:

AN:

75798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37168

Middle Eastern (MID)

AF:

0.000199

AC:

AN:

5024

European-Non Finnish (NFE)

AF:

0.00000762

AC:

AN:

1050284

Other (OTH)

AF:

0.000973

AC:

AN:

55506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

123

154

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:

0.00445

AC:

674

AN:

151544

Hom.:

Cov.:

AF XY:

0.00462

AC XY:

342

AN XY:

74058

show subpopulations

African (AFR)

AF:

0.0155

AC:

641

AN:

41420

American (AMR)

AF:

0.00144

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5040

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10500

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67734

Other (OTH)

AF:

0.00381

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

103

138

172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00210

Hom.:

Bravo

AF:

0.00549

ExAC

AF:

0.000350

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.28

T;T;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.0098

LIST_S2

Benign

0.57

T;T;T

MetaRNN

Benign

0.0045

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.;.

PhyloP100

0.20

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.55

N;N;N

REVEL

Benign

0.026

Sift

Benign

0.085

T;T;D

Sift4G

Benign

0.19

T;.;.

Polyphen

0.32

B;.;.

Vest4

0.087

MVP

0.39

MPC

0.44

ClinPred

0.0055

GERP RS

2.5

PromoterAI

-0.057

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.034

gMVP

0.24

Mutation Taster

=95/5

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

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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