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
Consequence
NM_006502.3 stop_gained, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 21 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLH | NM_006502.3 | c.490G>T | p.Glu164* | stop_gained, splice_region_variant | Exon 4 of 11 | ENST00000372236.9 | NP_006493.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLH | ENST00000372236.9 | c.490G>T | p.Glu164* | stop_gained, splice_region_variant | Exon 4 of 11 | 1 | NM_006502.3 | ENSP00000361310.4 | ||
POLH | ENST00000372226.1 | c.490G>T | p.Glu164* | stop_gained, splice_region_variant | Exon 4 of 11 | 1 | ENSP00000361300.1 | |||
POLH | ENST00000443535.1 | c.*89G>T | downstream_gene_variant | 2 | ENSP00000405320.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251352Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135866
GnomAD4 exome AF: 0.0000124 AC: 18AN: 1454196Hom.: 0 Cov.: 29 AF XY: 0.0000138 AC XY: 10AN XY: 723840
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74370
ClinVar
Submissions by phenotype
Xeroderma pigmentosum variant type Pathogenic:2Other:1
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Xeroderma pigmentosum Pathogenic:1
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at