6-43614018-A-G

Position:

• chr6-43614018-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006502.3(POLH):​c.1603A>G​(p.Lys535Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00075 in 1,614,140 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (13 hom.)
• Consequence: POLH NM_006502.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:2 U:1 B:5
• Conservation: PhyloP100: 1.34

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]

GTPBP2 (HGNC:4670): (GTP binding protein 2) GTP-binding proteins, or G proteins, constitute a superfamily capable of binding GTP or GDP. G proteins are activated by binding GTP and are inactivated by hydrolyzing GTP to GDP. This general mechanism enables G proteins to perform a wide range of biologic activities.[supplied by OMIM, Jan 2003]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030028075).
• BP6: Variant 6-43614018-A-G is Benign according to our data. Variant chr6-43614018-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 5894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-43614018-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000777 (1136/1461780) while in subpopulation EAS AF= 0.0208 (827/39700). AF 95% confidence interval is 0.0197. There are 13 homozygotes in gnomad4_exome. There are 571 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLH	NM_006502.3	c.1603A>G	p.Lys535Glu	missense_variant	11/11	ENST00000372236.9	NP_006493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLH	ENST00000372236.9	c.1603A>G	p.Lys535Glu	missense_variant	11/11	1	NM_006502.3	ENSP00000361310.4
POLH	ENST00000372226.1	c.*287A>G		3_prime_UTR_variant	11/11	1		ENSP00000361300.1
GTPBP2	ENST00000496137.5	n.*131+6101T>C		intron_variant		3		ENSP00000436973.1

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00865

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000873 AC: 219 AN: 250840 Hom.: 3 AF XY: 0.000834 AC XY: 113 AN XY: 135558

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00848

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000777 AC: 1136 AN: 1461780 Hom.: 13 Cov.: 32 AF XY: 0.000785 AC XY: 571 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.0208

Gnomad4 SAS exome AF: 0.000927

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000156

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000492 AC: 75 AN: 152360 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74502

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00867

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000539 Hom.: 1

Bravo AF: 0.000385

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00102 AC: 124

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:2 Uncertain:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum variant type Pathogenic:2 Uncertain:1 Benign:1

Pathogenic, flagged submission	literature only	OMIM	Dec 01, 2000	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely pathogenic, flagged submission	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Uncertain significance, flagged submission	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_006502.2:c.1603A>G in the POLH gene has an allele frequency of 0.008 in East Asian subpopulation in the gnomAD database. Benign computational verdict because benign predictions from DEOGEN2, EIGEN, FATHMM-MKL, PrimateAI and SIFT. It has been detected in heterozygous state in one individual with xeroderma pigmentosum (PMID: 11121129). We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PP4, BP4. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Sep 01, 2022

Variant summary: POLH c.1603A>G (p.Lys535Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00087 in 250840 control chromosomes (gnomAD), predominantly at a frequency of 0.0085 within the East Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 29 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLH causing Xeroderma Pigmentosum (0.0003), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Five ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, one as uncertain significance, one as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as benign. -

Xeroderma pigmentosum Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Mar 26, 2020

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

POLH-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.19
Sift	Benign	0.15	T
Sift4G	Benign	0.69	T
Polyphen		0.22	B
Vest4		0.75
MVP		0.62
MPC		0.61
ClinPred		0.029	T
GERP RS		3.3
Varity_R		0.22
gMVP		0.43

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

Other links and lift over

dbSNP: rs56307355; hg19: chr6-43581755;