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GeneBe

9-37422772-A-AAGGT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_012203.2(GRHPR):c.23_26dup(p.Phe10GlyfsTer12) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

GRHPR
NM_012203.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.05
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 81 pathogenic variants in the truncated region.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 9-37422772-A-AAGGT is Pathogenic according to our data. Variant chr9-37422772-A-AAGGT is described in ClinVar as [Pathogenic]. Clinvar id is 1074076.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GRHPRNM_012203.2 linkuse as main transcriptc.23_26dup p.Phe10GlyfsTer12 frameshift_variant 1/9 ENST00000318158.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GRHPRENST00000318158.11 linkuse as main transcriptc.23_26dup p.Phe10GlyfsTer12 frameshift_variant 1/91 NM_012203.2 P1Q9UBQ7-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeSep 02, 2020Loss-of-function variants in GRHPR are known to be pathogenic (PMID: 25644115). This sequence change creates a premature translational stop signal (p.Phe10Glyfs*12) in the GRHPR gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with GRHPR-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-37422769; API