9-37422763-C-T

Variant names:

• chr9-37422763-C-T
• rs979727637
• NM_012203.2:c.13C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_012203.2(GRHPR):​c.13C>T​(p.Arg5*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,437,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: GRHPR NM_012203.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.590
• Publications: 1 publications found

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]

GRHPR Gene-Disease associations (from GenCC):

• primary hyperoxaluria type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)

ENSG00000294170 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: 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 129 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-37422763-C-T is Pathogenic according to our data. Variant chr9-37422763-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 649477.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012203.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHPR	NM_012203.2	MANE Select	c.13C>T	p.Arg5*	stop_gained	Exon 1 of 9	NP_036335.1	A0A384N605

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHPR	ENST00000318158.11	TSL:1 MANE Select	c.13C>T	p.Arg5*	stop_gained	Exon 1 of 9	ENSP00000313432.6	Q9UBQ7-1
	GRHPR	ENST00000460882.5	TSL:1	n.68C>T		non_coding_transcript_exon	Exon 1 of 9
	GRHPR	ENST00000493368.5	TSL:1	n.98C>T		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1437884 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 713582

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32826

American (AMR) AF: 0.00 AC: 0 AN: 42358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25752

East Asian (EAS) AF: 0.00 AC: 0 AN: 38118

South Asian (SAS) AF: 0.00 AC: 0 AN: 82916

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4262

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1101814

Other (OTH) AF: 0.00 AC: 0 AN: 59276

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Benign	0.0090
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.27	N
PhyloP100		-0.59
Vest4		0.37
GERP RS		-0.98
PromoterAI		-0.38	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs979727637; hg19: chr9-37422760;