6-43614198-A-G

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.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. 16/21 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.645

Publications

23 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 links:

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]

GTPBP2 Gene-Disease associations (from GenCC):

Jaberi-Elahi syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

GTPBP2 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=0.00202626).

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.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLH	NM_006502.3 link	c.1783A>G	p.Met595Val	missense_variant	Exon 11 of 11	ENST00000372236.9	NP_006493.1	Q9Y253-1A0A024RD62
POLH	NM_001291969.2 link	c.1411A>G	p.Met471Val	missense_variant	Exon 9 of 9		NP_001278898.1	B3KN75
POLH	XM_047418900.1 link	c.1327A>G	p.Met443Val	missense_variant	Exon 8 of 8		XP_047274856.1
POLH	NM_001291970.2 link	c.*467A>G		3_prime_UTR_variant	Exon 11 of 11		NP_001278899.1	Q9Y253-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
POLH	ENST00000372236.9 link	c.1783A>G	p.Met595Val	missense_variant	Exon 11 of 11	1	NM_006502.3	ENSP00000361310.4	Q9Y253-1
POLH	ENST00000372226.1 link	c.*467A>G		3_prime_UTR_variant	Exon 11 of 11	1		ENSP00000361300.1	Q9Y253-2
GTPBP2	ENST00000496137.5 link	n.*131+5921T>C		intron_variant	Intron 3 of 3	3		ENSP00000436973.1	H0YF05

Frequencies

GnomAD3 genomes

AF:

0.0185

AC:

2818

AN:

152188

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0212

AC:

5322

AN:

251326

AF XY:

0.0228

show subpopulations

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 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.:

AF XY:

0.0266

AC XY:

19361

AN XY:

726680

show subpopulations

African (AFR)

AF:

0.00466

AC:

156

AN:

33460

American (AMR)

AF:

0.0166

AC:

744

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00842

AC:

220

AN:

26122

East Asian (EAS)

AF:

0.00139

AC:

AN:

39692

South Asian (SAS)

AF:

0.0374

AC:

3222

AN:

86252

European-Finnish (FIN)

AF:

0.00564

AC:

301

AN:

53414

Middle Eastern (MID)

AF:

0.00624

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0290

AC:

32263

AN:

1111322

Other (OTH)

AF:

0.0249

AC:

1503

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

2237

4475

6712

8950

11187

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1188

2376

3564

4752

5940

<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:

0.0185

AC:

2818

AN:

152306

Hom.:

Cov.:

AF XY:

0.0175

AC XY:

1305

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00496

AC:

206

AN:

41568

American (AMR)

AF:

0.0183

AC:

280

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3472

East Asian (EAS)

AF:

0.00309

AC:

AN:

5182

South Asian (SAS)

AF:

0.0425

AC:

205

AN:

4828

European-Finnish (FIN)

AF:

0.00414

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0291

AC:

1982

AN:

68024

Other (OTH)

AF:

0.0194

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

143

286

430

573

716

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0252

Hom.:

246

Bravo

AF:

0.0178

TwinsUK

AF:

0.0343

AC:

127

ALSPAC

AF:

0.0254

AC:

ESP6500AA

AF:

0.00567

AC:

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2021

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Xeroderma pigmentosum variant type

Benign:3

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

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:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 16, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 16823845, 27153395, 19477635) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.056

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.086

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

-0.65

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.46

REVEL

Benign

0.044

Sift

Benign

0.37

Sift4G

Benign

0.79

Polyphen

0.0

Vest4

0.019

MPC

0.21

ClinPred

0.0029

GERP RS

-6.8

Varity_R

0.045

gMVP

0.18

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

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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