rs757796926
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The ENST00000318158.11(GRHPR):c.404+5G>A variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.0000142 in 1,549,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )
Consequence
GRHPR
ENST00000318158.11 splice_donor_5th_base, intron
ENST00000318158.11 splice_donor_5th_base, intron
Scores
1
1
Splicing: ADA: 0.9995
2
Clinical Significance
Conservation
PhyloP100: 5.99
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 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Multiple lines of computational evidence support a deleterious effect 3: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai [when BayesDel_noAF was below the threshold]
PP5
Variant 9-37426659-G-A is Pathogenic according to our data. Variant chr9-37426659-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 548673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GRHPR | NM_012203.2 | c.404+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000318158.11 | NP_036335.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GRHPR | ENST00000318158.11 | c.404+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_012203.2 | ENSP00000313432 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251238Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135850
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GnomAD4 exome AF: 0.0000150 AC: 21AN: 1397044Hom.: 0 Cov.: 24 AF XY: 0.0000172 AC XY: 12AN XY: 698908
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74350
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary hyperoxaluria, type II Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 26, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 30, 2021 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 29, 2020 | - - |
Nephrocalcinosis;C0392525:Nephrolithiasis Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Sep 08, 2017 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 11, 2023 | ClinVar contains an entry for this variant (Variation ID: 548673). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has been observed in individuals with primary hyperoxaluria type II (PMID: 25644115, 28893421). This variant is present in population databases (rs757796926, gnomAD 0.0009%). 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. It affects a nucleotide within the consensus splice site. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 14
DS_DL_spliceai
Position offset: -5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at