NM_002583.4:c.1005G>T

Variant names:

• chr12-79592625-C-A
• rs8176908
• NM_002583.4:c.1005G>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002583.4(PAWR):​c.1005G>T​(p.Val335Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0075 in 769,000 control chromosomes in the GnomAD database, including 214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (148 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (66 hom.)
• Consequence: PAWR NM_002583.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.984
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 12-79592625-C-A is Benign according to our data. Variant chr12-79592625-C-A is described in ClinVar as Benign. ClinVar VariationId is 779530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.984 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0797 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.1005G>T	p.Val335Val	synonymous	Exon 7 of 7	NP_002574.2
	PAWR	NM_001354732.2		c.1005G>T	p.Val335Val	synonymous	Exon 7 of 7	NP_001341661.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAWR	ENST00000328827.9	TSL:1 MANE Select	c.1005G>T	p.Val335Val	synonymous	Exon 7 of 7	ENSP00000328088.4
	PAWR	ENST00000550603.1	TSL:5	c.198G>T	p.Val66Val	synonymous	Exon 3 of 4	ENSP00000447507.1
	PAWR	ENST00000547699.1	TSL:2	n.753G>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0235 AC: 3560 AN: 151778 Hom.: 141 Cov.: 32

Gnomad AFR AF: 0.0814

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00747

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00374

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000486

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00687 AC: 1634 AN: 237986 AF XY: 0.00550

Gnomad AFR exome AF: 0.0834

Gnomad AMR exome AF: 0.00358

Gnomad ASJ exome AF: 0.00242

Gnomad EAS exome AF: 0.0000567

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000313

Gnomad OTH exome AF: 0.00356

GnomAD4 exome AF: 0.00352 AC: 2173 AN: 617108 Hom.: 66 Cov.: 0 AF XY: 0.00322 AC XY: 1084 AN XY: 336616

African (AFR) AF: 0.0800 AC: 1350 AN: 16878

American (AMR) AF: 0.00388 AC: 157 AN: 40464

Ashkenazi Jewish (ASJ) AF: 0.00269 AC: 56 AN: 20838

East Asian (EAS) AF: 0.00 AC: 0 AN: 35742

South Asian (SAS) AF: 0.00414 AC: 277 AN: 66920

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51750

Middle Eastern (MID) AF: 0.00484 AC: 20 AN: 4128

European-Non Finnish (NFE) AF: 0.000253 AC: 88 AN: 347706

Other (OTH) AF: 0.00685 AC: 224 AN: 32682

GnomAD4 genome AF: 0.0237 AC: 3598 AN: 151892 Hom.: 148 Cov.: 32 AF XY: 0.0234 AC XY: 1739 AN XY: 74224

African (AFR) AF: 0.0820 AC: 3397 AN: 41408

American (AMR) AF: 0.00746 AC: 114 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00375 AC: 18 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000486 AC: 33 AN: 67958

Other (OTH) AF: 0.0138 AC: 29 AN: 2102

Alfa AF: 0.00612 Hom.: 43

Bravo AF: 0.0278

Asia WGS AF: 0.00665 AC: 24 AN: 3474

EpiCase AF: 0.000273

EpiControl AF: 0.000654

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	4.8
DANN	Benign	0.75
PhyloP100		0.98
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs8176908; hg19: chr12-79986405;