12-79690133-C-T

Variant names:

• chr12-79690133-C-T
• rs960054486
• NM_002583.4:c.112G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002583.4(PAWR):​c.112G>A​(p.Gly38Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000513 in 1,363,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: PAWR NM_002583.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.437

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10050407).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAWR	NM_002583.4	c.112G>A	p.Gly38Ser	missense_variant	Exon 2 of 7	ENST00000328827.9	NP_002574.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAWR	ENST00000328827.9	c.112G>A	p.Gly38Ser	missense_variant	Exon 2 of 7	1	NM_002583.4	ENSP00000328088.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000513 AC: 7 AN: 1363738 Hom.: 0 Cov.: 30 AF XY: 0.00000594 AC XY: 4 AN XY: 673296

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000296

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000469

Gnomad4 OTH exome AF: 0.0000176

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.112G>A (p.G38S) alteration is located in exon 2 (coding exon 1) of the PAWR gene. This alteration results from a G to A substitution at nucleotide position 112, causing the glycine (G) at amino acid position 38 to be replaced by a serine (S). 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	Benign	0.10
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T;T;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.63	T;T;T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.71	N;N;N
REVEL	Benign	0.021
Sift	Benign	0.10	T;D;D
Sift4G	Benign	0.80	T;.;.
Polyphen		0.0010	B;.;.
Vest4		0.14
MutPred		0.23		Gain of catalytic residue at P41 (P = 0);Gain of catalytic residue at P41 (P = 0);Gain of catalytic residue at P41 (P = 0);
MVP		0.33
MPC		1.2
ClinPred		0.11	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.041
gMVP		0.33

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: rs960054486; hg19: chr12-80083913;