rs3734690

Positions:

• chr6-43613849-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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/exons	MANE	Protein	UniProt
POLH	NM_006502.3	c.1434G>A	p.Thr478Thr	synonymous_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.1434G>A	p.Thr478Thr	synonymous_variant	11/11	1	NM_006502.3	ENSP00000361310.4
POLH	ENST00000372226.1	c.*118G>A		3_prime_UTR_variant	11/11	1		ENSP00000361300.1
GTPBP2	ENST00000496137.5	n.*131+6270C>T		intron_variant		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

GnomAD3 exomes AF: 0.0436 AC: 10958 AN: 251386 Hom.: 366 AF XY: 0.0447 AC XY: 6080 AN XY: 135900

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 SAS exome AF: 0.0852

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

Gnomad4 AFR exome AF: 0.116

Gnomad4 AMR exome AF: 0.0213

Gnomad4 ASJ exome AF: 0.0537

Gnomad4 EAS exome AF: 0.0336

Gnomad4 SAS exome AF: 0.0796

Gnomad4 FIN exome AF: 0.0365

Gnomad4 NFE exome AF: 0.0307

Gnomad4 OTH exome AF: 0.0408

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

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.0330

Gnomad4 ASJ AF: 0.0487

Gnomad4 EAS AF: 0.0365

Gnomad4 SAS AF: 0.0812

Gnomad4 FIN AF: 0.0383

Gnomad4 NFE AF: 0.0304

Gnomad4 OTH AF: 0.0432

Alfa AF: 0.0370 Hom.: 269

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	4.6
DANN	Benign	0.77

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