rs757796926

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

Scores

1
1
Splicing: ADA: 0.9995
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 5.99
Variant links:
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]

Genome browser will be placed here

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
GRHPRNM_012203.2 linkuse as main transcriptc.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
GRHPRENST00000318158.11 linkuse as main transcriptc.404+5G>A splice_donor_5th_base_variant, intron_variant 1 NM_012203.2 ENSP00000313432 P1Q9UBQ7-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152208
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251238
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135850
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000150
AC:
21
AN:
1397044
Hom.:
0
Cov.:
24
AF XY:
0.0000172
AC XY:
12
AN XY:
698908
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000199
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152208
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

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 submitterclinical testingBaylor GeneticsFeb 26, 2024- -
Likely pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsDec 30, 2021- -
Likely pathogenic, no assertion criteria providedclinical testingNatera, Inc.Oct 29, 2020- -
Nephrocalcinosis;C0392525:Nephrolithiasis Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyYale Center for Mendelian Genomics, Yale UniversitySep 08, 2017- -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 11, 2023ClinVar 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.26
CADD
Uncertain
23
DANN
Uncertain
0.98
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.99
SpliceAI score (max)
0.92
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.57
Position offset: 14
DS_DL_spliceai
0.92
Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs757796926; hg19: chr9-37426656; API