rs2307456

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006502.3(POLH):c.626G>T(p.Gly209Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00327 in 1,613,940 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 12 hom. )

Consequence

POLH
NM_006502.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 7.62

Publications

11 publications found

Variant links:

Genes affected

POLH (HGNC:9181): (DNA polymerase eta) This gene encodes a member of the Y family of specialized DNA polymerases. It copies undamaged DNA with a lower fidelity than other DNA-directed polymerases. However, it accurately replicates UV-damaged DNA; when thymine dimers are present, this polymerase inserts the complementary nucleotides in the newly synthesized DNA, thereby bypassing the lesion and suppressing the mutagenic effect of UV-induced DNA damage. This polymerase is thought to be involved in hypermutation during immunoglobulin class switch recombination. Mutations in this gene result in XPV, a variant type of xeroderma pigmentosum. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

POLH Gene-Disease associations (from GenCC):

xeroderma pigmentosum variant type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp

POLH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017212152).

BP6

Variant 6-43597831-G-T is Benign according to our data. Variant chr6-43597831-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0028 (427/152268) while in subpopulation SAS AF = 0.0108 (52/4832). AF 95% confidence interval is 0.00843. There are 4 homozygotes in GnomAd4. There are 252 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLH	NM_006502.3 link	c.626G>T	p.Gly209Val	missense_variant	Exon 5 of 11	ENST00000372236.9	NP_006493.1	Q9Y253-1A0A024RD62
POLH	NM_001291969.2 link	c.254G>T	p.Gly85Val	missense_variant	Exon 3 of 9		NP_001278898.1	B3KN75
POLH	NM_001291970.2 link	c.626G>T	p.Gly209Val	missense_variant	Exon 5 of 11		NP_001278899.1	Q9Y253-2
POLH	XM_047418900.1 link	c.170G>T	p.Gly57Val	missense_variant	Exon 2 of 8		XP_047274856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLH	ENST00000372236.9 link	c.626G>T	p.Gly209Val	missense_variant	Exon 5 of 11	1	NM_006502.3	ENSP00000361310.4		Q9Y253-1
POLH	ENST00000372226.1 link	c.626G>T	p.Gly209Val	missense_variant	Exon 5 of 11	1		ENSP00000361300.1		Q9Y253-2

Frequencies

GnomAD3 genomes

AF:

0.00281

AC:

427

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00125

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0108

Gnomad FIN

AF:

0.00951

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00307

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00378

AC:

951

AN:

251482

AF XY:

0.00433

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.00367

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00735

Gnomad NFE exome

AF:

0.00325

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00332

AC:

4852

AN:

1461672

Hom.:

Cov.:

AF XY:

0.00356

AC XY:

2591

AN XY:

727148

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33480

American (AMR)

AF:

0.00119

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00406

AC:

106

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0101

AC:

868

AN:

86256

European-Finnish (FIN)

AF:

0.00666

AC:

356

AN:

53416

Middle Eastern (MID)

AF:

0.00503

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00288

AC:

3203

AN:

1111804

Other (OTH)

AF:

0.00361

AC:

218

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

250

500

751

1001

1251

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

232

348

464

580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00280

AC:

427

AN:

152268

Hom.:

Cov.:

AF XY:

0.00338

AC XY:

252

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

41548

American (AMR)

AF:

0.00124

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.0108

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00951

AC:

101

AN:

10624

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00307

AC:

209

AN:

68020

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00267

Hom.:

Bravo

AF:

0.00224

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00341

AC:

414

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00507

EpiControl

AF:

0.00504

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Xeroderma pigmentosum variant type

Benign:5

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 17, 2017

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:4

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

POLH: BS1, BS2 -

May 06, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30414346) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 13, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: POLH c.626G>T (p.Gly209Val) results in a non-conservative amino acid change located in the UmuC domain (IPR001126) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0038 in 251482 control chromosomes, predominantly at a frequency of 0.01 within the South Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 34-fold of the estimated maximal expected allele frequency for a pathogenic variant in POLH causing Xeroderma Pigmentosum phenotype (0.0003), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.626G>T has been reported in the literature in individuals affected with melanoma and suspected HBOC (Potjer_2019, Moradian_2021). These reports do not provide unequivocal conclusions about association of the variant with Xeroderma Pigmentosum. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Xeroderma pigmentosum

Benign:1

Feb 18, 2021

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Malignant tumor of breast

Benign:1

Center of Medical Genetics and Primary Health Care

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

D;.

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.064

MetaRNN

Benign

0.017

T;T

MetaSVM

Uncertain

0.43

MutationAssessor

Pathogenic

4.2

H;H

PhyloP100

7.6

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-8.1

D;D

REVEL

Uncertain

0.62

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.64

MVP

0.96

MPC

0.87

ClinPred

0.12

GERP RS

5.4

Varity_R

0.90

gMVP

0.84

Mutation Taster

=53/47

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over