dbSNP rs533485700: PWP1:p.Ser464Cys (chr12-107710505-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007062.3(PWP1):c.1391C>G(p.Ser464Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000192 in 1,558,634 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S464F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 30)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

PWP1
NM_007062.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.38

Variant links:

Genes affected

PWP1 (HGNC:17015): (PWP1 homolog, endonuclein) The protein encoded by this gene contains several WD-40 repeats and is found mostly in the nucleus. The expression and localization of this protein are cell cycle dependent. Expression of this gene is upregulated in pancreatic adenocarcinoma. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2015]

PWP1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PWP1	NM_007062.3 link	c.1391C>G	p.Ser464Cys	missense_variant	Exon 14 of 15	ENST00000412830.8	NP_008993.1	Q13610-1A0A024RBH5
PWP1	NM_001317962.2 link	c.1205C>G	p.Ser402Cys	missense_variant	Exon 14 of 15		NP_001304891.1	B4DJV5
PWP1	NM_001317963.2 link	c.755C>G	p.Ser252Cys	missense_variant	Exon 14 of 15		NP_001304892.1	Q13610

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PWP1	ENST00000412830.8 link	c.1391C>G	p.Ser464Cys	missense_variant	Exon 14 of 15	1	NM_007062.3	ENSP00000387365.3		Q13610-1
PWP1	ENST00000541166.1 link	c.1205C>G	p.Ser402Cys	missense_variant	Exon 14 of 15	2		ENSP00000445249.1		B4DJV5

Frequencies

GnomAD3 genomes

AF:

0.0000135

AC:

AN:

147606

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000500

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.09e-7

AC:

AN:

1411028

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

701744

show subpopulations

Gnomad4 AFR exome

AF:

0.0000312

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000135

AC:

AN:

147606

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

71580

show subpopulations

Gnomad4 AFR

AF:

0.0000500

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.040

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.036

T;.

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.052

MetaRNN

Uncertain

0.62

D;D

MetaSVM

Uncertain

-0.21

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.5

N;N

REVEL

Benign

0.23

Sift

Benign

0.033

D;D

Sift4G

Benign

0.076

T;T

Polyphen

0.99

D;.

Vest4

0.53

MutPred

0.48

Loss of disorder (P = 0.0292);.;

MVP

0.91

MPC

0.78

ClinPred

0.91

GERP RS

5.8

Varity_R

0.19

gMVP

0.31

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over