rs2400546

Variant names:

• chr12-79670586-A-T
• rs2400546
• NM_002583.4:c.516+19143T>A

Variant summary

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

The NM_002583.4(PAWR):​c.516+19143T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 152,118 control chromosomes in the GnomAD database, including 10,801 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 0.23 (10801 hom., cov: 32)
• Consequence: PAWR NM_002583.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.43
• Publications: 2 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 (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.699 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.516+19143T>A		intron	N/A	NP_002574.2	Q96IZ0
	PAWR	NM_001354732.2		c.516+19143T>A		intron	N/A	NP_001341661.1	Q96IZ0
	PAWR	NM_001354733.2		c.516+19143T>A		intron	N/A	NP_001341662.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAWR	ENST00000328827.9	TSL:1 MANE Select	c.516+19143T>A		intron	N/A	ENSP00000328088.4	Q96IZ0
	PAWR	ENST00000903360.1		c.516+19143T>A		intron	N/A	ENSP00000573419.1
	PAWR	ENST00000912080.1		c.516+19143T>A		intron	N/A	ENSP00000582139.1

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34779 AN: 152000 Hom.: 10750 Cov.: 32

Gnomad AFR AF: 0.705

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.0671

Gnomad EAS AF: 0.213

Gnomad SAS AF: 0.0917

Gnomad FIN AF: 0.0199

Gnomad MID AF: 0.0732

Gnomad NFE AF: 0.0184

Gnomad OTH AF: 0.167

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.229 AC: 34885 AN: 152118 Hom.: 10801 Cov.: 32 AF XY: 0.224 AC XY: 16665 AN XY: 74374

African (AFR) AF: 0.706 AC: 29246 AN: 41436

American (AMR) AF: 0.128 AC: 1958 AN: 15284

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

East Asian (EAS) AF: 0.213 AC: 1102 AN: 5164

South Asian (SAS) AF: 0.0907 AC: 438 AN: 4828

European-Finnish (FIN) AF: 0.0199 AC: 211 AN: 10614

Middle Eastern (MID) AF: 0.0856 AC: 25 AN: 292

European-Non Finnish (NFE) AF: 0.0184 AC: 1251 AN: 68006

Other (OTH) AF: 0.168 AC: 354 AN: 2112

Alfa AF: 0.140 Hom.: 788

Bravo AF: 0.261

Asia WGS AF: 0.205 AC: 706 AN: 3450

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.86
DANN	Benign	0.57
PhyloP100		-1.4
Mutation Taster		=100/0	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: rs2400546; hg19: chr12-80064366;