Variant 5-75573739-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The ENST00000241436.9(POLK):c.410C>T(p.Ser137Phe) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

POLK
ENST00000241436.9 missense, splice_region

Scores

Splicing: ADA: 0.03488

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 5.01

Variant links:

Genes affected

POLK (HGNC:9183): (DNA polymerase kappa) This gene encodes a member of the DNA polymerase type-Y family of proteins. The encoded protein is a specialized DNA polymerase that catalyzes translesion DNA synthesis, which allows DNA replication in the presence of DNA lesions. Human cell lines lacking a functional copy of this gene exhibit impaired genome integrity and enhanced susceptibility to oxidative damage. Mutations in this gene that impair enzyme activity may be associated with prostate cancer in human patients. [provided by RefSeq, Sep 2016]

POLK links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a domain UmuC (size 255) in uniprot entity POLK_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000241436.9

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.839

PP5

Variant 5-75573739-C-T is Pathogenic according to our data. Variant chr5-75573739-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218231.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLK	NM_016218.6 linkuse as main transcript	c.410C>T	p.Ser137Phe	missense_variant, splice_region_variant	5/15	ENST00000241436.9
POLK	NR_170560.3 linkuse as main transcript	n.584C>T		splice_region_variant, non_coding_transcript_exon_variant	6/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLK	ENST00000241436.9 linkuse as main transcript	c.410C>T	p.Ser137Phe	missense_variant, splice_region_variant	5/15	1	NM_016218.6	P1	Q9UBT6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Malignant tumor of prostate

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Tulane Cancer Center, Tulane University

Jul 08, 2013

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

D;D;.;.;.

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Benign

0.076

MetaRNN

Pathogenic

0.84

D;D;D;D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Pathogenic

3.3

M;.;M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-4.9

D;D;D;D;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0020

D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

0.99

D;.;D;.;D

Vest4

0.85

MutPred

0.70

Loss of disorder (P = 0.0022);Loss of disorder (P = 0.0022);Loss of disorder (P = 0.0022);Loss of disorder (P = 0.0022);Loss of disorder (P = 0.0022);

MVP

0.94

MPC

0.41

ClinPred

0.99

GERP RS

3.0

Varity_R

0.89

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.035

dbscSNV1_RF

Benign

0.32

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over