6-43587489-G-T

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 22P and 1B. PVS1PM2PP3_StrongPP5_Very_StrongBS1_Supporting

The NM_006502.3(POLH):​c.490G>T​(p.Glu164*) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,606,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

POLH
NM_006502.3 stop_gained, splice_region

Scores

5
1
2
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 8.14
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 21 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 6-43587489-G-T is Pathogenic according to our data. Variant chr6-43587489-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-43587489-G-T is described in Lovd as [Pathogenic].
BS1
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000124 (18/1454196) while in subpopulation EAS AF= 0.000429 (17/39658). AF 95% confidence interval is 0.000273. There are 0 homozygotes in gnomad4_exome. There are 10 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLHNM_006502.3 linkc.490G>T p.Glu164* stop_gained, splice_region_variant Exon 4 of 11 ENST00000372236.9 NP_006493.1 Q9Y253-1A0A024RD62

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLHENST00000372236.9 linkc.490G>T p.Glu164* stop_gained, splice_region_variant Exon 4 of 11 1 NM_006502.3 ENSP00000361310.4 Q9Y253-1
POLHENST00000372226.1 linkc.490G>T p.Glu164* stop_gained, splice_region_variant Exon 4 of 11 1 ENSP00000361300.1 Q9Y253-2
POLHENST00000443535.1 linkc.*89G>T downstream_gene_variant 2 ENSP00000405320.1 Q5JTF2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152228
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251352
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135866
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000272
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000124
AC:
18
AN:
1454196
Hom.:
0
Cov.:
29
AF XY:
0.0000138
AC XY:
10
AN XY:
723840
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000429
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152228
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Xeroderma pigmentosum variant type Pathogenic:2Other:1
Mar 18, 2016
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: reference population

- -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Feb 23, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Xeroderma pigmentosum Pathogenic:1
Jun 16, 2019
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Glu164X variant in POLH has been reported in 9 homozygotes and 2 compound heterozygous individuals with Xeroderma pigmentosum variant type (XP-V) (Tanioka 2007, Inui 2008, Masaki 2008). It has also been identified in 0.03% (5/18392) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID: 225444). Although this is a nonsense variant, it is located in the last three bases of the exon, which is part of the 5’ splice region. Computational tools and in vitro splicing studies are consistent with pathogenicity (Tanioka 2007, Inui 2008). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive XP-V. ACMG/AMP Criteria applied: PVS1_Strong, PM3_Strong, PS3_Supporting. -

not provided Pathogenic:1
Jul 16, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 225444). This premature translational stop signal has been observed in individual(s) with xeroderma pigmentosum (PMID: 17344931). This variant is present in population databases (rs767433001, gnomAD 0.03%). This sequence change creates a premature translational stop signal (p.Glu164*) in the POLH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POLH are known to be pathogenic (PMID: 11773631, 24130121, 25256075). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.66
CADD
Pathogenic
51
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.99
FATHMM_MKL
Pathogenic
1.0
D
M_CAP
Benign
0.021
T
Vest4
0.83
GERP RS
5.6

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.99
SpliceAI score (max)
0.91
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.91
Position offset: 0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs767433001; hg19: chr6-43555226; API