12-79690193-C-G

Position:

chr12-79690193-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002583.4(PAWR):c.52G>C(p.Asp18His) variant causes a missense change. The variant allele was found at a frequency of 0.00000913 in 1,532,996 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000094 ( 0 hom. )

Consequence

PAWR
NM_002583.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.38

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:):

PPP1R12A-AS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAWR	NM_002583.4 linkuse as main transcript	c.52G>C	p.Asp18His	missense_variant	2/7	ENST00000328827.9	NP_002574.2	Q96IZ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PAWR	ENST00000328827.9 linkuse as main transcript	c.52G>C	p.Asp18His	missense_variant	2/7	1	NM_002583.4	ENSP00000328088.4	Q96IZ0
PAWR	ENST00000548426.1 linkuse as main transcript	c.52G>C	p.Asp18His	missense_variant	2/2	3		ENSP00000447454.1	F8W1M8
PAWR	ENST00000552637.1 linkuse as main transcript	c.52G>C	p.Asp18His	missense_variant	2/2	2		ENSP00000449928.1	A0A0B4J260
PPP1R12A-AS2	ENST00000551995.1 linkuse as main transcript	n.50C>G		non_coding_transcript_exon_variant	1/2	5

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000154

AC:

AN:

129666

Hom.:

AF XY:

0.0000277

AC XY:

AN XY:

72222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000869

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000941

AC:

AN:

1380992

Hom.:

Cov.:

AF XY:

0.0000190

AC XY:

AN XY:

682770

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.30e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152004

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000180

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2024

The c.52G>C (p.D18H) alteration is located in exon 2 (coding exon 1) of the PAWR gene. This alteration results from a G to C substitution at nucleotide position 52, causing the aspartic acid (D) at amino acid position 18 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Benign

0.90

DEOGEN2

Uncertain

0.75

D;T;.

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.82

T;T;T

M_CAP

Pathogenic

0.61

MetaRNN

Uncertain

0.54

D;D;D

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.8

L;.;.

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.7

D;D;D

REVEL

Benign

0.24

Sift

Uncertain

0.0050

D;D;D

Sift4G

Uncertain

0.012

D;.;.

Polyphen

0.95

P;.;.

Vest4

0.43

MutPred

0.39

Gain of catalytic residue at F19 (P = 5e-04);Gain of catalytic residue at F19 (P = 5e-04);Gain of catalytic residue at F19 (P = 5e-04);

MVP

0.75

MPC

1.4

ClinPred

0.93

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.37

gMVP

0.68

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over