rs9333555

chr6-43614198-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.1783A>G(p.Met595Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0256 in 1,613,394 control chromosomes in the GnomAD database, including 643 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (35 hom., cov: 32)
  • Exomes 𝑓: 0.026 (608 hom.)
• Consequence: POLH NM_006502.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.645

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:):

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=0.00202626).
• BP6: Variant 6-43614198-A-G is Benign according to our data. Variant chr6-43614198-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 259988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-43614198-A-G is described in Lovd as [Benign]. Variant chr6-43614198-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0185 (2818/152306) while in subpopulation SAS AF= 0.0425 (205/4828). AF 95% confidence interval is 0.0377. There are 35 homozygotes in gnomad4. There are 1305 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLH	NM_006502.3	c.1783A>G	p.Met595Val	missense_variant	11/11	ENST00000372236.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLH	ENST00000372236.9	c.1783A>G	p.Met595Val	missense_variant	11/11	1	NM_006502.3	P1
POLH	ENST00000372226.1	c.*467A>G		3_prime_UTR_variant	11/11	1
GTPBP2	ENST00000496137.5	c.*131+5921T>C		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2818 AN: 152188 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.00499

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.0424

Gnomad FIN AF: 0.00414

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0291

Gnomad OTH AF: 0.0196

GnomAD3 exomes AF: 0.0212 AC: 5322 AN: 251326 Hom.: 85 AF XY: 0.0228 AC XY: 3102 AN XY: 135838

Gnomad AFR exome AF: 0.00468

Gnomad AMR exome AF: 0.0160

Gnomad ASJ exome AF: 0.00805

Gnomad EAS exome AF: 0.00272

Gnomad SAS exome AF: 0.0391

Gnomad FIN exome AF: 0.00416

Gnomad NFE exome AF: 0.0278

Gnomad OTH exome AF: 0.0184

GnomAD4 exome AF: 0.0264 AC: 38500 AN: 1461088 Hom.: 608 Cov.: 33 AF XY: 0.0266 AC XY: 19361 AN XY: 726680

Gnomad4 AFR exome AF: 0.00466

Gnomad4 AMR exome AF: 0.0166

Gnomad4 ASJ exome AF: 0.00842

Gnomad4 EAS exome AF: 0.00139

Gnomad4 SAS exome AF: 0.0374

Gnomad4 FIN exome AF: 0.00564

Gnomad4 NFE exome AF: 0.0290

Gnomad4 OTH exome AF: 0.0249

GnomAD4 genome AF: 0.0185 AC: 2818 AN: 152306 Hom.: 35 Cov.: 32 AF XY: 0.0175 AC XY: 1305 AN XY: 74468

Gnomad4 AFR AF: 0.00496

Gnomad4 AMR AF: 0.0183

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.0425

Gnomad4 FIN AF: 0.00414

Gnomad4 NFE AF: 0.0291

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.0262 Hom.: 134

Bravo AF: 0.0178

TwinsUK AF: 0.0343 AC: 127

ALSPAC AF: 0.0254 AC: 98

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.0323 AC: 278

ExAC AF: 0.0224 AC: 2724

Asia WGS AF: 0.0290 AC: 101 AN: 3478

EpiCase AF: 0.0280

EpiControl AF: 0.0279

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Xeroderma pigmentosum variant type Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Likely Benign, for Xeroderma pigmentosum, variant type, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS1 => Allele frequency is greater than expected for disorder. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2019	This variant is associated with the following publications: (PMID: 16823845, 27153395, 19477635) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.056
Dann	Benign	0.46
DEOGEN2	Benign	0.086	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.044
Sift	Benign	0.37	T
Sift4G	Benign	0.79	T
Polyphen		0.0	B
Vest4		0.019
MPC		0.21
ClinPred		0.0029	T
GERP RS		-6.8
Varity_R		0.045
gMVP		0.18

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: rs9333555; hg19: chr6-43581935; COSMIC: COSV64778874;