rs2307456

Positions:

• chr6-43597831-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 7.62

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]

POLR1C (HGNC:20194): (RNA polymerase I and III subunit C) The protein encoded by this gene is a subunit of both RNA polymerase I and RNA polymerase III complexes. The encoded protein is part of the Pol core element. Mutations in this gene have been associated with Treacher Collins syndrome (TCS) and hypomyelinating leukodystrophy 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a domain UmuC (size 250) in uniprot entity POLH_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_006502.3
• 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 [Likely_benign]. Clinvar id is 259990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-43597831-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00332 (4852/1461672) while in subpopulation SAS AF= 0.0101 (868/86256). AF 95% confidence interval is 0.00951. There are 12 homozygotes in gnomad4_exome. There are 2591 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLH	NM_006502.3	c.626G>T	p.Gly209Val	missense_variant	5/11	ENST00000372236.9	NP_006493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLH	ENST00000372236.9	c.626G>T	p.Gly209Val	missense_variant	5/11	1	NM_006502.3	ENSP00000361310.4
POLH	ENST00000372226.1	c.626G>T	p.Gly209Val	missense_variant	5/11	1		ENSP00000361300.1

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 427 AN: 152150 Hom.: 4 Cov.: 32

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

GnomAD3 exomes AF: 0.00378 AC: 951 AN: 251482 Hom.: 3 AF XY: 0.00433 AC XY: 588 AN XY: 135914

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 SAS exome AF: 0.0101

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.: 12 Cov.: 31 AF XY: 0.00356 AC XY: 2591 AN XY: 727148

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00406

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0101

Gnomad4 FIN exome AF: 0.00666

Gnomad4 NFE exome AF: 0.00288

Gnomad4 OTH exome AF: 0.00361

GnomAD4 genome AF: 0.00280 AC: 427 AN: 152268 Hom.: 4 Cov.: 32 AF XY: 0.00338 AC XY: 252 AN XY: 74446

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0108

Gnomad4 FIN AF: 0.00951

Gnomad4 NFE AF: 0.00307

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00270 Hom.: 1

Bravo AF: 0.00224

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00341 AC: 414

Asia WGS AF: 0.00375 AC: 13 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

Submissions by phenotype

Xeroderma pigmentosum variant type Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Sep 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	POLH: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2019	This variant is associated with the following publications: (PMID: 30414346) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 13, 2022	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Xeroderma pigmentosum Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Feb 18, 2021

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.017	T;T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	4.2	H;H
PrimateAI	Benign	0.44	T
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	T
GERP RS		5.4
Varity_R		0.90
gMVP		0.84

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

LitVar

Other links and lift over

dbSNP: rs2307456; hg19: chr6-43565568;