9-37422793-A-C

Position:

• chr9-37422793-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000318158.11(GRHPR):​c.43A>C​(p.Ile15Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRHPR ENST00000318158.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19781512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRHPR	NM_012203.2	c.43A>C	p.Ile15Leu	missense_variant	1/9	ENST00000318158.11	NP_036335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRHPR	ENST00000318158.11	c.43A>C	p.Ile15Leu	missense_variant	1/9	1	NM_012203.2	ENSP00000313432	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 01, 2021

This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GRHPR protein function. This variant has not been reported in the literature in individuals with GRHPR-related conditions. This sequence change replaces isoleucine with leucine at codon 15 of the GRHPR protein (p.Ile15Leu). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.73	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.2	N;.
REVEL	Uncertain	0.32
Sift	Benign	0.23	T;.
Sift4G	Benign	0.65	T;T
Polyphen		0.0	B;.
Vest4		0.31
MutPred		0.56		Gain of disorder (P = 0.0516);Gain of disorder (P = 0.0516);
MVP		0.68
MPC		0.43
ClinPred		0.60	D
GERP RS		3.6
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.60
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1822894446; hg19: chr9-37422790;