rs180177309
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000318158.11(GRHPR):c.403_404+2delAAGT(p.Asn135fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000012 in 1,582,228 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 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 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
GRHPR
ENST00000318158.11 frameshift, splice_donor, splice_region, intron
ENST00000318158.11 frameshift, splice_donor, splice_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.26
Genes affected
GRHPR (HGNC:4570): (glyoxylate and hydroxypyruvate reductase) This gene encodes an enzyme with hydroxypyruvate reductase, glyoxylate reductase, and D-glycerate dehydrogenase enzymatic activities. The enzyme has widespread tissue expression and has a role in metabolism. Type II hyperoxaluria is caused by mutations in this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 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 9-37426652-GAAGT-G is Pathogenic according to our data. Variant chr9-37426652-GAAGT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 204250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37426652-GAAGT-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GRHPR | NM_012203.2 | c.404+3_404+6delAAGT | splice_region_variant, intron_variant | ENST00000318158.11 | NP_036335.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152190Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251320Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135878
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GnomAD4 exome AF: 0.0000119 AC: 17AN: 1430038Hom.: 0 AF XY: 0.0000154 AC XY: 11AN XY: 713524
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GnomAD4 genome 0.0000131 AC: 2AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74356
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary hyperoxaluria, type II Pathogenic:7Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 05, 2024 | - - |
| Pathogenic, no assertion criteria provided | research | Clinical Biochemistry Laboratory, Health Services Laboratory | Nov 27, 2014 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 19, 2019 | NM_012203.1(GRHPR):c.404+3_404+6delAAGT is classified as likely pathogenic in the context of primary hyperoxaluria type 2. Sources cited for classification include the following: PMID 24116921 and 14635115. Classification of NM_012203.1(GRHPR):c.404+3_404+6delAAGT is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations and the incidence of disease is extremely low. Please note: this variant was assessed in the context of healthy population screening. - |
| Pathogenic, no assertion criteria provided | research | Clinical Biochemistry Laboratory, Health Services Laboratory | Nov 27, 2014 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 03, 2018 | Variant summary: GRHPR c.404+3_404+6delAAGT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5 splicing donor site. These predictions have been confirmed by experimental evidence that this variant affects mRNA splicing (Cregeen_2003). The variant allele was found at a frequency of 2.8e-05 in 246140 control chromosomes. c.404+3_404+6delAAGT has been reported in the literature in multiple individuals affected with Primary Hyperoxaluria Type 2, and has been reported as a common pathogenic variants in individuals of Asian ancestry (Cregeen_2003, Webster_2000, Williams_2014). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 02, 2021 | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Chinese Inherited Urolithiasis Consortium, The Affiliated Yantai Yuhuangding Hospital of Qingdao University | Aug 26, 2024 | Variant_type:truncating/MutationTaster:NONE/CADD:NONE/phyloP:NONE/phastCons:NONE/gnomAD_exome_EastAsian:NONE/ExAC_EastAsian:NONE/dbSNP:NONE - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 05, 2023 | This sequence change falls in intron 4 of the GRHPR gene. It does not directly change the encoded amino acid sequence of the GRHPR protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs180177309, gnomAD 0.01%). This variant has been observed in individuals with primary hyperoxaluria type 2 (PMID: 11030416, 14635115). This variant is also known as c.403_405+2delAAGT. ClinVar contains an entry for this variant (Variation ID: 204250). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in altered splicing and introduces a premature termination codon (PMID: 14635115). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 21
DS_DL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at