9-37422751-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_012203.2(GRHPR):c.1A>T(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: GRHPR NM_012203.2 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• 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 14 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 554025
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-37422751-A-T is Pathogenic according to our data. Variant chr9-37422751-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556994.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary hyperoxaluria, type II Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Mar 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Benign	19
Dann	Benign	0.72
DEOGEN2	Benign	0.015	T;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	1.0	N;N
PROVEAN	Benign	-0.99	N;.
REVEL	Uncertain	0.47
Sift	Benign	0.064	T;.
Sift4G	Uncertain	0.045	D;D
Polyphen		0.0	B;.
Vest4		0.85
MutPred		0.98		Loss of disorder (P = 0.0881);Loss of disorder (P = 0.0881);
MVP		0.75
ClinPred		0.26	T
GERP RS		2.3
Varity_R		0.64
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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;