9-37422751-A-G

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PVS1 PS1_Moderate PM2 PP3 PP5_Very_Strong

The NM_012203.2(GRHPR):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000489 in 1,430,106 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: GRHPR NM_012203.2 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.15

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]

ACMG classification

Verdict is Pathogenic. Variant got 21 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_012203.2 (GRHPR) was described as [Likely_pathogenic] in ClinVar as 556994
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-37422751-A-G is Pathogenic according to our data. Variant chr9-37422751-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 554025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRHPR	NM_012203.2	c.1A>G	p.Met1?	start_lost	1/9	ENST00000318158.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRHPR	ENST00000318158.11	c.1A>G	p.Met1?	start_lost	1/9	1	NM_012203.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000489 AC: 7 AN: 1430106 Hom.: 0 Cov.: 31 AF XY: 0.00000705 AC XY: 5 AN XY: 708984

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: 0.0000366

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000364

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria, type II Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 22, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Uncertain	23
Dann	Benign	0.64
DEOGEN2	Benign	0.017	T;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	1.0	N;N
PROVEAN	Benign	-1.1	N;.
REVEL	Uncertain	0.44
Sift	Benign	0.076	T;.
Sift4G	Benign	0.14	T;T
Polyphen		0.0	B;.
Vest4		0.78
MutPred		0.98		Loss of disorder (P = 0.1053);Loss of disorder (P = 0.1053);
MVP		0.71
ClinPred		0.23	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.64		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554746094; hg19: chr9-37422748;