chr12-107710433-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_007062.3(PWP1):​c.1319C>T​(p.Pro440Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PWP1
NM_007062.3 missense

Scores

8
7
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.67
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.75

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PWP1NM_007062.3 linkc.1319C>T p.Pro440Leu missense_variant Exon 14 of 15 ENST00000412830.8 NP_008993.1 Q13610-1A0A024RBH5
PWP1NM_001317962.2 linkc.1133C>T p.Pro378Leu missense_variant Exon 14 of 15 NP_001304891.1 B4DJV5
PWP1NM_001317963.2 linkc.683C>T p.Pro228Leu missense_variant Exon 14 of 15 NP_001304892.1 Q13610

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PWP1ENST00000412830.8 linkc.1319C>T p.Pro440Leu missense_variant Exon 14 of 15 1 NM_007062.3 ENSP00000387365.3 Q13610-1
PWP1ENST00000541166.1 linkc.1133C>T p.Pro378Leu missense_variant Exon 14 of 15 2 ENSP00000445249.1 B4DJV5

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461278
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726962
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
30

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 28, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1319C>T (p.P440L) alteration is located in exon 14 (coding exon 14) of the PWP1 gene. This alteration results from a C to T substitution at nucleotide position 1319, causing the proline (P) at amino acid position 440 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.41
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.16
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.18
T;.
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Benign
0.060
D
MetaRNN
Pathogenic
0.75
D;D
MetaSVM
Benign
-0.32
T
MutationAssessor
Pathogenic
3.2
M;.
PrimateAI
Uncertain
0.58
T
PROVEAN
Pathogenic
-9.1
D;D
REVEL
Uncertain
0.54
Sift
Uncertain
0.0040
D;D
Sift4G
Uncertain
0.0020
D;D
Polyphen
1.0
D;.
Vest4
0.67
MutPred
0.59
Gain of sheet (P = 0.1208);.;
MVP
0.70
MPC
0.50
ClinPred
1.0
D
GERP RS
5.8
Varity_R
0.63
gMVP
0.73

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-108104210; API