rs56307355

Variant names:

• chr6-43614018-A-G
• rs56307355
• NM_006502.3:c.1603A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-43614018-A-G
• chr6-43614018-A-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006502.3(POLH):​c.1603A>G​(p.Lys535Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00075 in 1,614,140 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. K535K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (13 hom.)
• Consequence: POLH NM_006502.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:2 U:1 B:6
• Conservation: PhyloP100: 1.34
• Publications: 15 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, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030028075).
• BP6: Variant 6-43614018-A-G is Benign according to our data. Variant chr6-43614018-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 5894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000492 (75/152360) while in subpopulation EAS AF = 0.00867 (45/5192). AF 95% confidence interval is 0.00666. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

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.1603A>G	p.Lys535Glu	missense	Exon 11 of 11	NP_006493.1	Q9Y253-1
	POLH	NM_001291969.2		c.1231A>G	p.Lys411Glu	missense	Exon 9 of 9	NP_001278898.1
	POLH	NM_001291970.2		c.*287A>G		3_prime_UTR	Exon 11 of 11	NP_001278899.1	Q9Y253-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLH	ENST00000372236.9	TSL:1 MANE Select	c.1603A>G	p.Lys535Glu	missense	Exon 11 of 11	ENSP00000361310.4	Q9Y253-1
	POLH	ENST00000372226.1	TSL:1	c.*287A>G		3_prime_UTR	Exon 11 of 11	ENSP00000361300.1	Q9Y253-2
	POLH	ENST00000921322.1		c.1603A>G	p.Lys535Glu	missense	Exon 12 of 12	ENSP00000591381.1

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00865

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000873 AC: 219 AN: 250840 AF XY: 0.000834

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00848

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000777 AC: 1136 AN: 1461780 Hom.: 13 Cov.: 32 AF XY: 0.000785 AC XY: 571 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26136

East Asian (EAS) AF: 0.0208 AC: 827 AN: 39700

South Asian (SAS) AF: 0.000927 AC: 80 AN: 86258

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53320

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.000156 AC: 174 AN: 1112004

Other (OTH) AF: 0.000629 AC: 38 AN: 60396

GnomAD4 genome AF: 0.000492 AC: 75 AN: 152360 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74502

African (AFR) AF: 0.0000240 AC: 1 AN: 41580

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00867 AC: 45 AN: 5192

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68038

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000705 Hom.: 1

Bravo AF: 0.000385

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00102 AC: 124

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	1	1	Xeroderma pigmentosum variant type (4)
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	POLH-related disorder (1)
-	-	1	Xeroderma pigmentosum (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.3
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.19
Sift	Benign	0.15	T
Sift4G	Benign	0.69	T
Polyphen		0.22	B
Vest4		0.75
MVP		0.62
MPC		0.61
ClinPred		0.029	T
GERP RS		3.3
Varity_R		0.22
gMVP		0.43
Mutation Taster		=78/22	disease causing (ClinVar)

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: rs56307355; hg19: chr6-43581755;