rs1554059573

chr5-75573841-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The ENST00000241436.9(POLK):c.512T>C(p.Phe171Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLK ENST00000241436.9 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.99

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 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, 0.958
• PP5: Variant 5-75573841-T-C is Pathogenic according to our data. Variant chr5-75573841-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 218233.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLK	NM_016218.6	c.512T>C	p.Phe171Ser	missense_variant	5/15	ENST00000241436.9
POLK	NR_170560.3	n.686T>C		non_coding_transcript_exon_variant	6/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLK	ENST00000241436.9	c.512T>C	p.Phe171Ser	missense_variant	5/15	1	NM_016218.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Malignant tumor of prostate Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Tulane Cancer Center, Tulane University

Mar 20, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.6	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.5	D;D;D;D
REVEL	Pathogenic	0.87
Sift	Benign	0.049	D;D;D;D
Sift4G	Uncertain	0.038	D;D;D;T
Polyphen		1.0	D;D;.;P
Vest4		0.96
MutPred		0.81		Gain of disorder (P = 0.0048);Gain of disorder (P = 0.0048);Gain of disorder (P = 0.0048);Gain of disorder (P = 0.0048);
MVP		0.94
MPC		0.54
ClinPred		0.99	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1554059573; hg19: chr5-74869666;