9-37422766-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012203.2(GRHPR):c.16C>T(p.Leu6Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,593,940 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (36 hom.)
• Consequence: GRHPR NM_012203.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.28

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0075918436).
• BP6: Variant 9-37422766-C-T is Benign according to our data. Variant chr9-37422766-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 366851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0013 (198/152322) while in subpopulation SAS AF= 0.0139 (67/4824). AF 95% confidence interval is 0.0112. There are 2 homozygotes in gnomad4. There are 121 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRHPR	NM_012203.2	c.16C>T	p.Leu6Phe	missense_variant	1/9	ENST00000318158.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRHPR	ENST00000318158.11	c.16C>T	p.Leu6Phe	missense_variant	1/9	1	NM_012203.2	P1

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 197 AN: 152204 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00321 AC: 703 AN: 218716 Hom.: 6 AF XY: 0.00401 AC XY: 477 AN XY: 118934

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00540

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0174

Gnomad FIN exome AF: 0.0000542

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.00332

GnomAD4 exome AF: 0.00222 AC: 3204 AN: 1441618 Hom.: 36 Cov.: 31 AF XY: 0.00274 AC XY: 1964 AN XY: 715688

Gnomad4 AFR exome AF: 0.000182

Gnomad4 AMR exome AF: 0.00115

Gnomad4 ASJ exome AF: 0.00620

Gnomad4 EAS exome AF: 0.0000521

Gnomad4 SAS exome AF: 0.0178

Gnomad4 FIN exome AF: 0.0000590

Gnomad4 NFE exome AF: 0.00113

Gnomad4 OTH exome AF: 0.00316

GnomAD4 genome AF: 0.00130 AC: 198 AN: 152322 Hom.: 2 Cov.: 32 AF XY: 0.00162 AC XY: 121 AN XY: 74484

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00750

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00138 Hom.: 2

Bravo AF: 0.00116

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00175 AC: 15

ExAC AF: 0.00309 AC: 372

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria, type II Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2020	- -

GRHPR-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 31, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.041	T;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.74	T;T
MetaRNN	Benign	0.0076	T;T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.9	M;.
MutationTaster	Benign	0.81	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.5	N;.
REVEL	Uncertain	0.30
Sift	Benign	0.036	D;.
Sift4G	Benign	0.066	T;T
Polyphen		0.29	B;.
Vest4		0.26
MVP		0.85
MPC		0.62
ClinPred		0.097	T
GERP RS		4.0
Varity_R		0.27
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs147185003; hg19: chr9-37422763;