rs121908563
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_006502.3(POLH):c.376C>T(p.Gln126Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
POLH
NM_006502.3 stop_gained
NM_006502.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.48
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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;
PP5
?
Variant 6-43587375-C-T is Pathogenic according to our data. Variant chr6-43587375-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5889.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLH | NM_006502.3 | c.376C>T | p.Gln126Ter | stop_gained | 4/11 | ENST00000372236.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLH | ENST00000372236.9 | c.376C>T | p.Gln126Ter | stop_gained | 4/11 | 1 | NM_006502.3 | P1 | |
POLH | ENST00000372226.1 | c.376C>T | p.Gln126Ter | stop_gained | 4/11 | 1 | |||
POLH | ENST00000443535.1 | c.190C>T | p.Gln64Ter | stop_gained | 3/3 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251486Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135918
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461690Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727158
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Xeroderma pigmentosum variant type Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 09, 1999 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 15, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 5889). This premature translational stop signal has been observed in individual(s) with xeroderma pigmentosum (Invitae). This variant is present in population databases (rs121908563, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Gln126*) 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at