12-79621127-A-T

Variant names:

• chr12-79621127-A-T
• rs2307223
• NM_002583.4:c.597T>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_002583.4(PAWR):​c.597T>A​(p.Ile199Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.759 in 1,607,414 control chromosomes in the GnomAD database, including 480,746 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.63 (34752 hom., cov: 31)
  • Exomes 𝑓: 0.77 (445994 hom.)
• Consequence: PAWR NM_002583.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.128
• Publications: 26 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]

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.046).
• BP7: Synonymous conserved (PhyloP=0.128 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.811 is higher than 0.05.

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.597T>A	p.Ile199Ile	synonymous	Exon 3 of 7	NP_002574.2	Q96IZ0
	PAWR	NM_001354732.2		c.597T>A	p.Ile199Ile	synonymous	Exon 3 of 7	NP_001341661.1	Q96IZ0
	PAWR	NM_001354733.2		c.597T>A	p.Ile199Ile	synonymous	Exon 3 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.597T>A	p.Ile199Ile	synonymous	Exon 3 of 7	ENSP00000328088.4	Q96IZ0
	PAWR	ENST00000903360.1		c.597T>A	p.Ile199Ile	synonymous	Exon 2 of 6	ENSP00000573419.1
	PAWR	ENST00000912080.1		c.597T>A	p.Ile199Ile	synonymous	Exon 3 of 7	ENSP00000582139.1

Frequencies

GnomAD3 genomes AF: 0.630 AC: 95751 AN: 152014 Hom.: 34760 Cov.: 31

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.766

Gnomad AMR AF: 0.724

Gnomad ASJ AF: 0.679

Gnomad EAS AF: 0.500

Gnomad SAS AF: 0.582

Gnomad FIN AF: 0.814

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.817

Gnomad OTH AF: 0.672

GnomAD2 exomes AF: 0.705 AC: 176588 AN: 250542 AF XY: 0.709

Gnomad AFR exome AF: 0.240

Gnomad AMR exome AF: 0.734

Gnomad ASJ exome AF: 0.682

Gnomad EAS exome AF: 0.478

Gnomad FIN exome AF: 0.822

Gnomad NFE exome AF: 0.808

Gnomad OTH exome AF: 0.733

GnomAD4 exome AF: 0.773 AC: 1124886 AN: 1455282 Hom.: 445994 Cov.: 30 AF XY: 0.769 AC XY: 556946 AN XY: 724456

African (AFR) AF: 0.228 AC: 7599 AN: 33342

American (AMR) AF: 0.734 AC: 32805 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.685 AC: 17881 AN: 26094

East Asian (EAS) AF: 0.413 AC: 16398 AN: 39660

South Asian (SAS) AF: 0.597 AC: 51369 AN: 86090

European-Finnish (FIN) AF: 0.825 AC: 43274 AN: 52474

Middle Eastern (MID) AF: 0.586 AC: 3371 AN: 5754

European-Non Finnish (NFE) AF: 0.821 AC: 908363 AN: 1107012

Other (OTH) AF: 0.729 AC: 43826 AN: 60152

GnomAD4 genome AF: 0.629 AC: 95746 AN: 152132 Hom.: 34752 Cov.: 31 AF XY: 0.629 AC XY: 46813 AN XY: 74372

African (AFR) AF: 0.254 AC: 10536 AN: 41530

American (AMR) AF: 0.724 AC: 11046 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.679 AC: 2355 AN: 3470

East Asian (EAS) AF: 0.499 AC: 2576 AN: 5162

South Asian (SAS) AF: 0.583 AC: 2805 AN: 4810

European-Finnish (FIN) AF: 0.814 AC: 8623 AN: 10590

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.817 AC: 55536 AN: 67992

Other (OTH) AF: 0.667 AC: 1411 AN: 2116

Alfa AF: 0.289 Hom.: 3958

EpiCase AF: 0.800

EpiControl AF: 0.791

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	4.3
DANN	Benign	0.72
PhyloP100		0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	polymorphism (auto)

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: rs2307223; hg19: chr12-80014907; COSMIC: COSV60921724;