dbSNP rs8176908: PAWR:p.Val335Val (chr12-79592625-C-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.984

Publications

1 publications found

Variant links:

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]

PAWR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAWR	NM_002583.4 link	c.1005G>T	p.Val335Val	synonymous_variant	Exon 7 of 7	ENST00000328827.9	NP_002574.2	Q96IZ0
PAWR	NM_001354732.2 link	c.1005G>T	p.Val335Val	synonymous_variant	Exon 7 of 7		NP_001341661.1
PAWR	XM_047428916.1 link	c.1005G>T	p.Val335Val	synonymous_variant	Exon 6 of 6		XP_047284872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAWR	ENST00000328827.9 link	c.1005G>T	p.Val335Val	synonymous_variant	Exon 7 of 7	1	NM_002583.4	ENSP00000328088.4		Q96IZ0

Frequencies

GnomAD3 genomes

AF:

0.0235

AC:

3560

AN:

151778

Hom.:

141

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.00322

AC XY:

1084

AN XY:

336616

show subpopulations

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:

AN:

20838

East Asian (EAS)

AF:

0.00

AC:

AN:

35742

South Asian (SAS)

AF:

0.00414

AC:

277

AN:

66920

European-Finnish (FIN)

AF:

0.0000193

AC:

AN:

51750

Middle Eastern (MID)

AF:

0.00484

AC:

AN:

4128

European-Non Finnish (NFE)

AF:

0.000253

AC:

AN:

347706

Other (OTH)

AF:

0.00685

AC:

224

AN:

32682

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

172

259

345

431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0237

AC:

3598

AN:

151892

Hom.:

148

Cov.:

AF XY:

0.0234

AC XY:

1739

AN XY:

74224

show subpopulations

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:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00375

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000486

AC:

AN:

67958

Other (OTH)

AF:

0.0138

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

170

340

509

679

849

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00612

Hom.:

Bravo

AF:

0.0278

Asia WGS

AF:

0.00665

AC:

AN:

3474

EpiCase

AF:

0.000273

EpiControl

AF:

0.000654

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

4.8

(source)

DANN

Benign

0.75

PhyloP100

0.98

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over