6-43587489-G-A

Variant names:

• chr6-43587489-G-A
• rs767433001
• NM_006502.3:c.490G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006502.3(POLH):​c.490G>A​(p.Glu164Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLH NM_006502.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.14
• Publications: 5 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.490G>A	p.Glu164Lys	missense splice_region	Exon 4 of 11	NP_006493.1
	POLH	NM_001291970.2		c.490G>A	p.Glu164Lys	missense splice_region	Exon 4 of 11	NP_001278899.1
	POLH	NM_001291969.2		c.118+4348G>A		intron	N/A	NP_001278898.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLH	ENST00000372236.9	TSL:1 MANE Select	c.490G>A	p.Glu164Lys	missense splice_region	Exon 4 of 11	ENSP00000361310.4
	POLH	ENST00000372226.1	TSL:1	c.490G>A	p.Glu164Lys	missense splice_region	Exon 4 of 11	ENSP00000361300.1
	POLH	ENST00000443535.1	TSL:2	c.*89G>A		downstream_gene	N/A	ENSP00000405320.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	2.0	M
PhyloP100		8.1
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.29
Sift	Benign	0.048	D
Sift4G	Uncertain	0.031	D
Polyphen		0.080	B
Vest4		0.50
MutPred		0.51		Gain of methylation at E164 (P = 0.0112)
MVP		0.78
MPC		0.25
ClinPred		0.83	D
GERP RS		5.6
Varity_R		0.44
gMVP		0.67
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.90		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs767433001; hg19: chr6-43555226;