rs3734690

Variant names:

• chr6-43613849-G-A
• rs3734690
• NM_006502.3:c.1434G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006502.3(POLH):​c.1434G>A​(p.Thr478Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0381 in 1,614,068 control chromosomes in the GnomAD database, including 1,646 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (320 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1326 hom.)
• Consequence: POLH NM_006502.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.697
• Publications: 9 publications found

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]

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)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 6-43613849-G-A is Benign according to our data. Variant chr6-43613849-G-A is described in ClinVar as Benign. ClinVar VariationId is 259987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.697 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLH	NM_006502.3	c.1434G>A	p.Thr478Thr	synonymous_variant	Exon 11 of 11	ENST00000372236.9	NP_006493.1
POLH	NM_001291969.2	c.1062G>A	p.Thr354Thr	synonymous_variant	Exon 9 of 9		NP_001278898.1
POLH	XM_047418900.1	c.978G>A	p.Thr326Thr	synonymous_variant	Exon 8 of 8		XP_047274856.1
POLH	NM_001291970.2	c.*118G>A		3_prime_UTR_variant	Exon 11 of 11		NP_001278899.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLH	ENST00000372236.9	c.1434G>A	p.Thr478Thr	synonymous_variant	Exon 11 of 11	1	NM_006502.3	ENSP00000361310.4
POLH	ENST00000372226.1	c.*118G>A		3_prime_UTR_variant	Exon 11 of 11	1		ENSP00000361300.1
GTPBP2	ENST00000496137.5	n.*131+6270C>T		intron_variant	Intron 3 of 3	3		ENSP00000436973.1

Frequencies

GnomAD3 genomes AF: 0.0542 AC: 8250 AN: 152092 Hom.: 319 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0330

Gnomad ASJ AF: 0.0487

Gnomad EAS AF: 0.0364

Gnomad SAS AF: 0.0811

Gnomad FIN AF: 0.0383

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0304

Gnomad OTH AF: 0.0427

GnomAD2 exomes AF: 0.0436 AC: 10958 AN: 251386 AF XY: 0.0447

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.0190

Gnomad ASJ exome AF: 0.0528

Gnomad EAS exome AF: 0.0382

Gnomad FIN exome AF: 0.0387

Gnomad NFE exome AF: 0.0313

Gnomad OTH exome AF: 0.0425

GnomAD4 exome AF: 0.0364 AC: 53263 AN: 1461858 Hom.: 1326 Cov.: 32 AF XY: 0.0376 AC XY: 27360 AN XY: 727234

African (AFR) AF: 0.116 AC: 3873 AN: 33478

American (AMR) AF: 0.0213 AC: 954 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0537 AC: 1403 AN: 26136

East Asian (EAS) AF: 0.0336 AC: 1335 AN: 39698

South Asian (SAS) AF: 0.0796 AC: 6867 AN: 86258

European-Finnish (FIN) AF: 0.0365 AC: 1947 AN: 53408

Middle Eastern (MID) AF: 0.0572 AC: 330 AN: 5768

European-Non Finnish (NFE) AF: 0.0307 AC: 34088 AN: 1111994

Other (OTH) AF: 0.0408 AC: 2466 AN: 60394

GnomAD4 genome AF: 0.0543 AC: 8267 AN: 152210 Hom.: 320 Cov.: 32 AF XY: 0.0555 AC XY: 4134 AN XY: 74424

African (AFR) AF: 0.107 AC: 4424 AN: 41528

American (AMR) AF: 0.0330 AC: 504 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0487 AC: 169 AN: 3472

East Asian (EAS) AF: 0.0365 AC: 189 AN: 5184

South Asian (SAS) AF: 0.0812 AC: 391 AN: 4818

European-Finnish (FIN) AF: 0.0383 AC: 406 AN: 10606

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0304 AC: 2065 AN: 68018

Other (OTH) AF: 0.0432 AC: 91 AN: 2108

Alfa AF: 0.0409 Hom.: 577

Bravo AF: 0.0559

Asia WGS AF: 0.0710 AC: 246 AN: 3478

EpiCase AF: 0.0330

EpiControl AF: 0.0336

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

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 13, 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
BayesDel_noAF	Benign	-0.70
CADD	Benign	4.6
DANN	Benign	0.77
PhyloP100		-0.70
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3734690; hg19: chr6-43581586; COSMIC: COSV64780689;