12-107692850-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001317963.2(PWP1):​c.-309C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000149 in 1,613,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

PWP1
NM_001317963.2 5_prime_UTR_premature_start_codon_gain

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.80
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3562656).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PWP1NM_007062.3 linkc.356C>T p.Thr119Met missense_variant Exon 4 of 15 ENST00000412830.8 NP_008993.1 Q13610-1A0A024RBH5
PWP1NM_001317963.2 linkc.-309C>T 5_prime_UTR_premature_start_codon_gain_variant Exon 4 of 15 NP_001304892.1 Q13610
PWP1NM_001317962.2 linkc.170C>T p.Thr57Met missense_variant Exon 4 of 15 NP_001304891.1 B4DJV5
PWP1NM_001317963.2 linkc.-309C>T 5_prime_UTR_variant Exon 4 of 15 NP_001304892.1 Q13610

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PWP1ENST00000412830.8 linkc.356C>T p.Thr119Met missense_variant Exon 4 of 15 1 NM_007062.3 ENSP00000387365.3 Q13610-1

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152146
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251236
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135796
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1461496
Hom.:
0
Cov.:
29
AF XY:
0.00000825
AC XY:
6
AN XY:
727048
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:
0.0000187
Gnomad4 NFE exome
AF:
0.0000108
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152146
Hom.:
0
Cov.:
33
AF XY:
0.0000673
AC XY:
5
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00144
Alfa
AF:
0.000211
Hom.:
0
Bravo
AF:
0.0000907
ExAC
AF:
0.00000824
AC:
1
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 03, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.356C>T (p.T119M) alteration is located in exon 4 (coding exon 4) of the PWP1 gene. This alteration results from a C to T substitution at nucleotide position 356, causing the threonine (T) at amino acid position 119 to be replaced by a methionine (M). 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
Benign
0.14
BayesDel_addAF
Benign
0.0018
T
BayesDel_noAF
Benign
-0.13
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.021
T;T;.
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.86
D;T;D
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.36
T;T;T
MetaSVM
Benign
-0.53
T
MutationAssessor
Benign
2.0
M;.;.
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-1.6
N;D;N
REVEL
Benign
0.24
Sift
Benign
0.23
T;T;T
Sift4G
Benign
0.15
T;D;T
Polyphen
0.54
P;.;.
Vest4
0.24
MutPred
0.40
Loss of sheet (P = 0.007);.;.;
MVP
0.82
MPC
0.38
ClinPred
0.50
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.076
gMVP
0.32

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.

Other links and lift over

dbSNP: rs769546991; hg19: chr12-108086627; COSMIC: COSV69833146; API