9-37422784-A-G

Variant names:

• chr9-37422784-A-G
• rs761847384
• NM_012203.2:c.34A>G

Variant summary

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

The NM_012203.2(GRHPR):​c.34A>G​(p.Thr12Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000387 in 1,445,310 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T12T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000039 (1 hom.)
• Consequence: GRHPR NM_012203.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided U:1 B:1
• Conservation: PhyloP100: 5.82

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRHPR	NM_012203.2	c.34A>G	p.Thr12Ala	missense_variant	Exon 1 of 9	ENST00000318158.11	NP_036335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRHPR	ENST00000318158.11	c.34A>G	p.Thr12Ala	missense_variant	Exon 1 of 9	1	NM_012203.2	ENSP00000313432.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000629 AC: 14 AN: 222536 Hom.: 1 AF XY: 0.000107 AC XY: 13 AN XY: 121342

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000498

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000387 AC: 56 AN: 1445310 Hom.: 1 Cov.: 31 AF XY: 0.0000599 AC XY: 43 AN XY: 717840

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: 0.000547

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000168

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000498 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The GRHPR p.T12A variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs761847384) and in control databases in 14 of 222536 chromosomes (1 homozygous) at a frequency of 0.00006291, and was only observed in the South Asian population in 14 of 28138  chromosomes (freq: 0.0004975) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.T12 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Primary hyperoxaluria, type II Benign:1

Oct 09, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;T
Eigen	Benign	0.093
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Uncertain	0.078	D
MutationAssessor	Uncertain	2.0	M;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.0	D;.
REVEL	Uncertain	0.56
Sift	Benign	0.053	T;.
Sift4G	Benign	0.083	T;D
Polyphen		0.39	B;.
Vest4		0.62
MutPred		0.43		Loss of phosphorylation at T12 (P = 0.0477);Loss of phosphorylation at T12 (P = 0.0477);
MVP		0.84
MPC		0.91
ClinPred		0.32	T
GERP RS		4.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.72
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs761847384; hg19: chr9-37422781;