rs758304537
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_138413.4(HOGA1):c.208C>T(p.Arg70*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,613,662 control chromosomes in the GnomAD database, including 1 homozygotes. 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
Consequence
NM_138413.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HOGA1 | ENST00000370646.9 | c.208C>T | p.Arg70* | stop_gained | Exon 1 of 7 | 1 | NM_138413.4 | ENSP00000359680.4 | ||
ENSG00000249967 | ENST00000370649.3 | c.208C>T | p.Arg70* | stop_gained | Exon 1 of 10 | 2 | ENSP00000359683.3 | |||
HOGA1 | ENST00000370647.8 | c.208C>T | p.Arg70* | stop_gained | Exon 1 of 3 | 1 | ENSP00000359681.4 | |||
HOGA1 | ENST00000465608.1 | n.589C>T | non_coding_transcript_exon_variant | Exon 1 of 3 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152144Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000403 AC: 10AN: 248150Hom.: 1 AF XY: 0.0000595 AC XY: 8AN XY: 134382
GnomAD4 exome AF: 0.0000376 AC: 55AN: 1461518Hom.: 1 Cov.: 31 AF XY: 0.0000344 AC XY: 25AN XY: 727062
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74314
ClinVar
Submissions by phenotype
Primary hyperoxaluria type 3 Pathogenic:9
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ACMG: PVS1 PM2 PM3 -
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Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). The variant has been reported to be associated with HOGA1 related disorder (ClinVar ID: VCV000204269 / PMID: 22391140). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
The missense c.208C>T (p.Arg70Ter) variant in HOGA1 gene has been reported previously in compound heterozygous state in individuals affected with primary hyperoxaluria type III (Williams et al. 2012; Williams et al. 2015; Richard et al. 2017). The c.208C>T variant is reported with an allele frequency of 0.004% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Uncertain Significance / Pathognic (multiple submissions). The nucleotide change c.208C>T in HOGA1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -
Variant summary: HOGA1 c.208C>T (p.Arg70X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-05 in 248150 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in HOGA1 causing Primary Hyperoxaluria, Type III (4e-05 vs 0.0015), allowing no conclusion about variant significance. c.208C>T has been reported in the literature in multiple compound heterozygous individuals affected with Primary Hyperoxaluria, Type III (e.g. Martin-Higueras_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33865885). ClinVar contains an entry for this variant (Variation ID: 204269). Based on the evidence outlined above, the variant was classified as pathogenic. -
Variant_type:missense/MutationTaster:Disease_causing_automatic/CADD:Damaging/phyloP:Nonconserved/phastCons:Conserved/gnomAD_exome_EastAsian:0/ExAC_EastAsian:0/dbSNP:rs758304537 -
not provided Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg70*) in the HOGA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HOGA1 are known to be pathogenic (PMID: 22391140, 22781098). This variant is present in population databases (rs758304537, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with primary hyperoxaluria type 3 (PMID: 22391140, 25629080, 27742850). ClinVar contains an entry for this variant (Variation ID: 204269). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at