6-43585614-A-G

Variant names:

• chr6-43585614-A-G
• rs9472084
• NM_006502.3:c.273-1658A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006502.3(POLH):​c.273-1658A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 148,908 control chromosomes in the GnomAD database, including 5,367 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (5367 hom., cov: 30)
• Consequence: POLH NM_006502.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.250
• Publications: 7 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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.495 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.273-1658A>G		intron	N/A	NP_006493.1	Q9Y253-1
	POLH	NM_001291969.2		c.118+2473A>G		intron	N/A	NP_001278898.1
	POLH	NM_001291970.2		c.273-1658A>G		intron	N/A	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.273-1658A>G		intron	N/A	ENSP00000361310.4	Q9Y253-1
	POLH	ENST00000372226.1	TSL:1	c.273-1658A>G		intron	N/A	ENSP00000361300.1	Q9Y253-2
	POLH	ENST00000921322.1		c.273-1658A>G		intron	N/A	ENSP00000591381.1

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27131 AN: 148818 Hom.: 5348 Cov.: 30

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.0276

Gnomad AMR AF: 0.0973

Gnomad ASJ AF: 0.0592

Gnomad EAS AF: 0.0378

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.0375

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0610

Gnomad OTH AF: 0.156

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.183 AC: 27195 AN: 148908 Hom.: 5367 Cov.: 30 AF XY: 0.178 AC XY: 12957 AN XY: 72654

African (AFR) AF: 0.501 AC: 19872 AN: 39684

American (AMR) AF: 0.0972 AC: 1460 AN: 15020

Ashkenazi Jewish (ASJ) AF: 0.0592 AC: 204 AN: 3448

East Asian (EAS) AF: 0.0379 AC: 194 AN: 5124

South Asian (SAS) AF: 0.124 AC: 588 AN: 4740

European-Finnish (FIN) AF: 0.0375 AC: 377 AN: 10046

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0611 AC: 4126 AN: 67576

Other (OTH) AF: 0.156 AC: 322 AN: 2070

Alfa AF: 0.0787 Hom.: 1077

Bravo AF: 0.206

Asia WGS AF: 0.117 AC: 405 AN: 3444

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.22
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism (auto)

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: rs9472084; hg19: chr6-43553351;