rs2307223

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-79621127-A-C
• chr12-79621127-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002583.4(PAWR):​c.597T>G​(p.Ile199Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0662 in 1,608,512 control chromosomes in the GnomAD database, including 22,372 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.23 (10850 hom., cov: 31)
  • Exomes 𝑓: 0.049 (11522 hom.)
• Consequence: PAWR NM_002583.4 missense
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2461969E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.7 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAWR	NM_002583.4	MANE Select	c.597T>G	p.Ile199Met	missense	Exon 3 of 7	NP_002574.2
	PAWR	NM_001354732.2		c.597T>G	p.Ile199Met	missense	Exon 3 of 7	NP_001341661.1
	PAWR	NM_001354733.2		c.597T>G	p.Ile199Met	missense	Exon 3 of 5	NP_001341662.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAWR	ENST00000328827.9	TSL:1 MANE Select	c.597T>G	p.Ile199Met	missense	Exon 3 of 7	ENSP00000328088.4
	PAWR	ENST00000551712.1	TSL:3	c.432T>G	p.Ile144Met	missense	Exon 2 of 4	ENSP00000448317.1
	PAWR	ENST00000550006.1	TSL:3	n.481T>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34865 AN: 152042 Hom.: 10799 Cov.: 31

Gnomad AFR AF: 0.706

Gnomad AMI AF: 0.0736

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.0671

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.0914

Gnomad FIN AF: 0.0201

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0184

Gnomad OTH AF: 0.167

GnomAD2 exomes AF: 0.105 AC: 26214 AN: 250542 AF XY: 0.0904

Gnomad AFR exome AF: 0.722

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.0633

Gnomad EAS exome AF: 0.230

Gnomad FIN exome AF: 0.0193

Gnomad NFE exome AF: 0.0196

Gnomad OTH exome AF: 0.0682

GnomAD4 exome AF: 0.0491 AC: 71481 AN: 1456352 Hom.: 11522 Cov.: 30 AF XY: 0.0479 AC XY: 34736 AN XY: 724916

African (AFR) AF: 0.733 AC: 24444 AN: 33334

American (AMR) AF: 0.115 AC: 5144 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0656 AC: 1712 AN: 26102

East Asian (EAS) AF: 0.228 AC: 9054 AN: 39648

South Asian (SAS) AF: 0.0849 AC: 7310 AN: 86118

European-Finnish (FIN) AF: 0.0184 AC: 967 AN: 52506

Middle Eastern (MID) AF: 0.0953 AC: 549 AN: 5760

European-Non Finnish (NFE) AF: 0.0155 AC: 17166 AN: 1108000

Other (OTH) AF: 0.0853 AC: 5135 AN: 60190

GnomAD4 genome AF: 0.230 AC: 34971 AN: 152160 Hom.: 10850 Cov.: 31 AF XY: 0.225 AC XY: 16712 AN XY: 74380

African (AFR) AF: 0.706 AC: 29331 AN: 41528

American (AMR) AF: 0.128 AC: 1954 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0671 AC: 233 AN: 3470

East Asian (EAS) AF: 0.214 AC: 1105 AN: 5164

South Asian (SAS) AF: 0.0905 AC: 436 AN: 4820

European-Finnish (FIN) AF: 0.0201 AC: 213 AN: 10596

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0184 AC: 1251 AN: 68004

Other (OTH) AF: 0.168 AC: 356 AN: 2116

Alfa AF: 0.284 Hom.: 3958

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.655 AC: 2888

ESP6500EA AF: 0.0149 AC: 128

ExAC AF: 0.115 AC: 13979

EpiCase AF: 0.0213

EpiControl AF: 0.0225

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	1.9
DANN	Benign	0.12
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.071	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.76	N
PhyloP100		0.13
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.066
Sift	Benign	1.0	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.028
MPC		0.42
ClinPred		0.0015	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.023
gMVP		0.050
Mutation Taster		=95/5	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: COSV60923628;