9-37429817-A-G

Variant names:

• chr9-37429817-A-G
• rs309458
• NM_012203.2:c.579A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_012203.2(GRHPR):​c.579A>G​(p.Ala193Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.904 in 1,602,214 control chromosomes in the GnomAD database, including 656,388 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (57067 hom., cov: 35)
  • Exomes 𝑓: 0.91 (599321 hom.)
• Consequence: GRHPR NM_012203.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:10 O:1
• Conservation: PhyloP100: -3.32

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 9-37429817-A-G is Benign according to our data. Variant chr9-37429817-A-G is described in ClinVar as [Benign]. Clinvar id is 21490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37429817-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRHPR	NM_012203.2	c.579A>G	p.Ala193Ala	synonymous_variant	Exon 6 of 9	ENST00000318158.11	NP_036335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRHPR	ENST00000318158.11	c.579A>G	p.Ala193Ala	synonymous_variant	Exon 6 of 9	1	NM_012203.2	ENSP00000313432.6

Frequencies

GnomAD3 genomes AF: 0.862 AC: 131215 AN: 152150 Hom.: 57029 Cov.: 35

Gnomad AFR AF: 0.747

Gnomad AMI AF: 0.879

Gnomad AMR AF: 0.884

Gnomad ASJ AF: 0.909

Gnomad EAS AF: 0.921

Gnomad SAS AF: 0.917

Gnomad FIN AF: 0.877

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.913

Gnomad OTH AF: 0.883

GnomAD3 exomes AF: 0.894 AC: 224605 AN: 251230 Hom.: 100684 AF XY: 0.900 AC XY: 122219 AN XY: 135802

Gnomad AFR exome AF: 0.742

Gnomad AMR exome AF: 0.864

Gnomad ASJ exome AF: 0.904

Gnomad EAS exome AF: 0.924

Gnomad SAS exome AF: 0.921

Gnomad FIN exome AF: 0.882

Gnomad NFE exome AF: 0.914

Gnomad OTH exome AF: 0.903

GnomAD4 exome AF: 0.909 AC: 1317530 AN: 1449946 Hom.: 599321 Cov.: 30 AF XY: 0.910 AC XY: 656870 AN XY: 722142

Gnomad4 AFR exome AF: 0.745

Gnomad4 AMR exome AF: 0.866

Gnomad4 ASJ exome AF: 0.903

Gnomad4 EAS exome AF: 0.907

Gnomad4 SAS exome AF: 0.921

Gnomad4 FIN exome AF: 0.882

Gnomad4 NFE exome AF: 0.916

Gnomad4 OTH exome AF: 0.905

GnomAD4 genome AF: 0.862 AC: 131304 AN: 152268 Hom.: 57067 Cov.: 35 AF XY: 0.864 AC XY: 64311 AN XY: 74460

Gnomad4 AFR AF: 0.747

Gnomad4 AMR AF: 0.884

Gnomad4 ASJ AF: 0.909

Gnomad4 EAS AF: 0.921

Gnomad4 SAS AF: 0.918

Gnomad4 FIN AF: 0.877

Gnomad4 NFE AF: 0.913

Gnomad4 OTH AF: 0.882

Alfa AF: 0.906 Hom.: 89116

Bravo AF: 0.857

Asia WGS AF: 0.900 AC: 3130 AN: 3478

EpiCase AF: 0.922

EpiControl AF: 0.921

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria, type II Uncertain:1 Benign:3 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 27, 2014

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: in vitro

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:4

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is a RefSeq error. The reference base (c.579A) is the minor allele. This al lele (A) has been identified in 25.9% (2685/10378) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs309 458) and thus meets criteria to be classified as benign. -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.0
DANN	Benign	0.63

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: rs309458; hg19: chr9-37429814; COSMIC: COSV58944398; COSMIC: COSV58944398;