rs6941583

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006502.3(POLH):c.1939A>T(p.Met647Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0491 in 1,612,354 control chromosomes in the GnomAD database, including 5,137 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M647R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.11 ( 2157 hom., cov: 32)

Exomes 𝑓: 0.042 ( 2980 hom. )

Consequence

POLH
NM_006502.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.90

Publications

29 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=0.0013748407).

BP6

Variant 6-43614354-A-T is Benign according to our data. Variant chr6-43614354-A-T is described in ClinVar as Benign. ClinVar VariationId is 259989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLH	NM_006502.3 link	c.1939A>T	p.Met647Leu	missense_variant	Exon 11 of 11	ENST00000372236.9	NP_006493.1	Q9Y253-1A0A024RD62
POLH	NM_001291969.2 link	c.1567A>T	p.Met523Leu	missense_variant	Exon 9 of 9		NP_001278898.1	B3KN75
POLH	XM_047418900.1 link	c.1483A>T	p.Met495Leu	missense_variant	Exon 8 of 8		XP_047274856.1
POLH	NM_001291970.2 link	c.*623A>T		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.1939A>T	p.Met647Leu	missense_variant	Exon 11 of 11	1	NM_006502.3	ENSP00000361310.4	Q9Y253-1
POLH	ENST00000372226.1 link	c.*623A>T		3_prime_UTR_variant	Exon 11 of 11	1		ENSP00000361300.1	Q9Y253-2
GTPBP2	ENST00000496137.5 link	n.*131+5765T>A		intron_variant	Intron 3 of 3	3		ENSP00000436973.1	H0YF05

Frequencies

GnomAD3 genomes

AF:

0.113

AC:

17193

AN:

152102

Hom.:

2139

Cov.:

show subpopulations

Gnomad AFR

AF:

0.310

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0570

Gnomad ASJ

AF:

0.0490

Gnomad EAS

AF:

0.0366

Gnomad SAS

AF:

0.0826

Gnomad FIN

AF:

0.0380

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0310

Gnomad OTH

AF:

0.0899

GnomAD2 exomes

AF:

0.0591

AC:

14840

AN:

251254

AF XY:

0.0560

show subpopulations

Gnomad AFR exome

AF:

0.321

Gnomad AMR exome

AF:

0.0284

Gnomad ASJ exome

AF:

0.0538

Gnomad EAS exome

AF:

0.0391

Gnomad FIN exome

AF:

0.0388

Gnomad NFE exome

AF:

0.0318

Gnomad OTH exome

AF:

0.0509

GnomAD4 exome

AF:

0.0424

AC:

61839

AN:

1460134

Hom.:

2980

Cov.:

AF XY:

0.0428

AC XY:

31042

AN XY:

726010

show subpopulations

African (AFR)

AF:

0.321

AC:

10745

AN:

33428

American (AMR)

AF:

0.0327

AC:

1459

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.0552

AC:

1440

AN:

26108

East Asian (EAS)

AF:

0.0340

AC:

1346

AN:

39636

South Asian (SAS)

AF:

0.0800

AC:

6899

AN:

86234

European-Finnish (FIN)

AF:

0.0365

AC:

1948

AN:

53408

Middle Eastern (MID)

AF:

0.0681

AC:

392

AN:

5760

European-Non Finnish (NFE)

AF:

0.0309

AC:

34310

AN:

1110570

Other (OTH)

AF:

0.0547

AC:

3300

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

3407

6815

10222

13630

17037

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1524

3048

4572

6096

7620

<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:

0.113

AC:

17262

AN:

152220

Hom.:

2157

Cov.:

AF XY:

0.112

AC XY:

8316

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.311

AC:

12894

AN:

41478

American (AMR)

AF:

0.0570

AC:

872

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0490

AC:

170

AN:

3472

East Asian (EAS)

AF:

0.0367

AC:

190

AN:

5176

South Asian (SAS)

AF:

0.0825

AC:

398

AN:

4824

European-Finnish (FIN)

AF:

0.0380

AC:

404

AN:

10622

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0310

AC:

2111

AN:

68022

Other (OTH)

AF:

0.0899

AC:

190

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

646

1292

1938

2584

3230

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

336

504

672

840

<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:

0.0463

Hom.:

287

Bravo

AF:

0.123

TwinsUK

AF:

0.0283

AC:

105

ALSPAC

AF:

0.0304

AC:

117

ESP6500AA

AF:

0.305

AC:

1343

ESP6500EA

AF:

0.0308

AC:

265

ExAC

AF:

0.0654

AC:

7941

Asia WGS

AF:

0.0850

AC:

297

AN:

3478

EpiCase

AF:

0.0337

EpiControl

AF:

0.0344

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Xeroderma pigmentosum variant type

Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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. -

not provided

Benign:2

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.070

Eigen

Benign

-0.12

Eigen_PC

Benign

0.070

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0014

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PhyloP100

2.9

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.23

REVEL

Benign

0.14

Sift

Benign

0.51

Sift4G

Benign

0.61

Polyphen

0.030

Vest4

0.11

MutPred

0.19

Loss of catalytic residue at M647 (P = 0.1213);

MPC

0.20

ClinPred

0.016

GERP RS

5.7

Varity_R

0.41

gMVP

0.47

Mutation Taster

=91/9

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