rs2307456

Variant names:

• chr6-43597831-G-T
• rs2307456
• NM_006502.3:c.626G>T

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.626G>T​(p.Gly209Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00327 in 1,613,940 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (12 hom.)
• Consequence: POLH NM_006502.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 7.62
• Publications: 11 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]

POLH Gene-Disease associations (from GenCC):

• xeroderma pigmentosum variant type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.017212152).
• BP6: Variant 6-43597831-G-T is Benign according to our data. Variant chr6-43597831-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0028 (427/152268) while in subpopulation SAS AF = 0.0108 (52/4832). AF 95% confidence interval is 0.00843. There are 4 homozygotes in GnomAd4. There are 252 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLH	NM_006502.3	MANE Select	c.626G>T	p.Gly209Val	missense	Exon 5 of 11	NP_006493.1
	POLH	NM_001291969.2		c.254G>T	p.Gly85Val	missense	Exon 3 of 9	NP_001278898.1
	POLH	NM_001291970.2		c.626G>T	p.Gly209Val	missense	Exon 5 of 11	NP_001278899.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLH	ENST00000372236.9	TSL:1 MANE Select	c.626G>T	p.Gly209Val	missense	Exon 5 of 11	ENSP00000361310.4
	POLH	ENST00000372226.1	TSL:1	c.626G>T	p.Gly209Val	missense	Exon 5 of 11	ENSP00000361300.1
	POLH	ENST00000921322.1		c.626G>T	p.Gly209Val	missense	Exon 6 of 12	ENSP00000591381.1

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 427 AN: 152150 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00951

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00307

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00378 AC: 951 AN: 251482 AF XY: 0.00433

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00735

Gnomad NFE exome AF: 0.00325

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00332 AC: 4852 AN: 1461672 Hom.: 12 Cov.: 31 AF XY: 0.00356 AC XY: 2591 AN XY: 727148

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.00119 AC: 53 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00406 AC: 106 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0101 AC: 868 AN: 86256

European-Finnish (FIN) AF: 0.00666 AC: 356 AN: 53416

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5768

European-Non Finnish (NFE) AF: 0.00288 AC: 3203 AN: 1111804

Other (OTH) AF: 0.00361 AC: 218 AN: 60388

GnomAD4 genome AF: 0.00280 AC: 427 AN: 152268 Hom.: 4 Cov.: 32 AF XY: 0.00338 AC XY: 252 AN XY: 74446

African (AFR) AF: 0.000481 AC: 20 AN: 41548

American (AMR) AF: 0.00124 AC: 19 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4832

European-Finnish (FIN) AF: 0.00951 AC: 101 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00307 AC: 209 AN: 68020

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00267 Hom.: 1

Bravo AF: 0.00224

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00341 AC: 414

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00507

EpiControl AF: 0.00504

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Xeroderma pigmentosum variant type (5)
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Malignant tumor of breast (1)
-	-	1	Xeroderma pigmentosum (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		7.6
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-8.1	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.64
MVP		0.96
MPC		0.87
ClinPred		0.12	T
GERP RS		5.4
Varity_R		0.90
gMVP		0.84
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2307456; hg19: chr6-43565568;