chr6-43585614-A-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_006502.3(POLH):​c.273-1658A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000127 in 149,064 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00013 (0 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLH	NM_006502.3	c.273-1658A>C		intron_variant	Intron 3 of 10	ENST00000372236.9	NP_006493.1
POLH	NM_001291969.2	c.118+2473A>C		intron_variant	Intron 2 of 8		NP_001278898.1
POLH	NM_001291970.2	c.273-1658A>C		intron_variant	Intron 3 of 10		NP_001278899.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLH	ENST00000372236.9	c.273-1658A>C		intron_variant	Intron 3 of 10	1	NM_006502.3	ENSP00000361310.4
POLH	ENST00000372226.1	c.273-1658A>C		intron_variant	Intron 3 of 10	1		ENSP00000361300.1
POLH	ENST00000443535.1	c.87-1658A>C		intron_variant	Intron 2 of 2	2		ENSP00000405320.1

Frequencies

GnomAD3 genomes AF: 0.000128 AC: 19 AN: 148974 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000378

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000666

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000444

Gnomad OTH AF: 0.00

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

GnomAD4 genome AF: 0.000127 AC: 19 AN: 149064 Hom.: 0 Cov.: 30 AF XY: 0.000110 AC XY: 8 AN XY: 72720

African (AFR) AF: 0.000377 AC: 15 AN: 39796

American (AMR) AF: 0.0000665 AC: 1 AN: 15034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10058

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

European-Non Finnish (NFE) AF: 0.0000444 AC: 3 AN: 67592

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.00 Hom.: 1077

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.1
DANN	Benign	0.21
PhyloP100		-0.25

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: rs9472084; hg19: chr6-43553351;