NM_002583.4:c.112G>A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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. 14/22 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
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002583.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAWR	NM_002583.4	MANE Select	c.112G>A	p.Gly38Ser	missense	Exon 2 of 7	NP_002574.2	Q96IZ0
	PAWR	NM_001354732.2		c.112G>A	p.Gly38Ser	missense	Exon 2 of 7	NP_001341661.1	Q96IZ0
	PAWR	NM_001354733.2		c.112G>A	p.Gly38Ser	missense	Exon 2 of 5	NP_001341662.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAWR	ENST00000328827.9	TSL:1 MANE Select	c.112G>A	p.Gly38Ser	missense	Exon 2 of 7	ENSP00000328088.4	Q96IZ0
	PAWR	ENST00000903360.1		c.112G>A	p.Gly38Ser	missense	Exon 1 of 6	ENSP00000573419.1
	PAWR	ENST00000912080.1		c.112G>A	p.Gly38Ser	missense	Exon 2 of 7	ENSP00000582139.1

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

African (AFR) AF: 0.00 AC: 0 AN: 28296

American (AMR) AF: 0.0000296 AC: 1 AN: 33728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24222

East Asian (EAS) AF: 0.00 AC: 0 AN: 31460

South Asian (SAS) AF: 0.00 AC: 0 AN: 78308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5278

European-Non Finnish (NFE) AF: 0.00000469 AC: 5 AN: 1067074

Other (OTH) AF: 0.0000176 AC: 1 AN: 56788

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.44
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.021
Sift	Benign	0.10	T
Sift4G	Benign	0.80	T
Polyphen		0.0010	B
Vest4		0.14
MutPred		0.23		Gain of catalytic residue at P41 (P = 0)
MVP		0.33
MPC		1.2
ClinPred		0.11	T
GERP RS		1.8
PromoterAI		-0.00090	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.041
gMVP		0.33
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs960054486; hg19: chr12-80083913;