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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006502.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLH	NM_006502.3	MANE Select	c.1434G>A	p.Thr478Thr	synonymous	Exon 11 of 11	NP_006493.1
	POLH	NM_001291969.2		c.1062G>A	p.Thr354Thr	synonymous	Exon 9 of 9	NP_001278898.1
	POLH	NM_001291970.2		c.*118G>A		3_prime_UTR	Exon 11 of 11	NP_001278899.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLH	ENST00000372236.9	TSL:1 MANE Select	c.1434G>A	p.Thr478Thr	synonymous	Exon 11 of 11	ENSP00000361310.4
	POLH	ENST00000372226.1	TSL:1	c.*118G>A		3_prime_UTR	Exon 11 of 11	ENSP00000361300.1
	POLH	ENST00000921322.1		c.1434G>A	p.Thr478Thr	synonymous	Exon 12 of 12	ENSP00000591381.1

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Xeroderma pigmentosum variant type (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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;