rs8176804

chr12-79690120-G-Achr12-79690120-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

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. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0044 (6 hom., cov: 31)
  • Exomes 𝑓: 0.00040 (2 hom.)
• Consequence: PAWR NM_002583.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.201

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]

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

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044992566).
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome 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 gnomad4_exome. There are 216 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 672 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAWR	NM_002583.4	c.125C>T	p.Pro42Leu	missense_variant	2/7	ENST00000328827.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAWR	ENST00000328827.9	c.125C>T	p.Pro42Leu	missense_variant	2/7	1	NM_002583.4	P1
PPP1R12A-AS2	ENST00000551995.1			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00444 AC: 672 AN: 151432 Hom.: 6 Cov.: 31

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

GnomAD3 exomes AF: 0.000561 AC: 51 AN: 90954 Hom.: 0 AF XY: 0.000501 AC XY: 26 AN XY: 51860

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 SAS exome AF: 0.00

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.: 2 Cov.: 30 AF XY: 0.000328 AC XY: 216 AN XY: 659090

Gnomad4 AFR exome AF: 0.0163

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000132

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000762

Gnomad4 OTH exome AF: 0.000973

GnomAD4 genome AF: 0.00445 AC: 674 AN: 151544 Hom.: 6 Cov.: 31 AF XY: 0.00462 AC XY: 342 AN XY: 74058

Gnomad4 AFR AF: 0.0155

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.00381

Alfa AF: 0.00175 Hom.: 1

Bravo AF: 0.00549

ExAC AF: 0.000350 AC: 27

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	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	14
Dann	Benign	0.94
DEOGEN2	Benign	0.28	T;T;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.0098	N
LIST_S2	Benign	0.57	T;T;T
MetaRNN	Benign	0.0045	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.80	D
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	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.034
gMVP		0.24

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

Other links and lift over

dbSNP: rs8176804; hg19: chr12-80083900;