Genetic Variant GRHPR:p.Pro3Gln (chr9-37422758-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_012203.2(GRHPR):c.8C>A(p.Pro3Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,434,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P3L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

GRHPR
NM_012203.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.813

Publications

0 publications found

Variant links:

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]

GRHPR Gene-Disease associations (from GenCC):

primary hyperoxaluria type 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)

GRHPR links:

ENSG00000294170 (HGNC:):

ENSG00000294170 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012203.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHPR	NM_012203.2	MANE Select	c.8C>A	p.Pro3Gln	missense	Exon 1 of 9	NP_036335.1	A0A384N605

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRHPR	ENST00000318158.11	TSL:1 MANE Select	c.8C>A	p.Pro3Gln	missense	Exon 1 of 9	ENSP00000313432.6	Q9UBQ7-1
GRHPR	ENST00000460882.5	TSL:1	n.63C>A		non_coding_transcript_exon	Exon 1 of 9
GRHPR	ENST00000493368.5	TSL:1	n.93C>A		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.97e-7

AC:

AN:

1434644

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

711700

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32712

American (AMR)

AF:

0.00

AC:

AN:

41890

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25716

East Asian (EAS)

AF:

0.0000264

AC:

AN:

37858

South Asian (SAS)

AF:

0.00

AC:

AN:

82588

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4260

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1100156

Other (OTH)

AF:

0.00

AC:

AN:

59148

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.020

Eigen

Benign

-0.86

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.58

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.2

PhyloP100

-0.81

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.73

REVEL

Uncertain

0.34

Sift

Uncertain

0.026

Sift4G

Uncertain

0.014

Polyphen

0.71

Vest4

0.16

MutPred

0.49

Loss of catalytic residue at P3 (P = 0.0596)

MVP

0.68

MPC

0.40

ClinPred

0.58

GERP RS

-4.2

PromoterAI

-0.49

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.038

gMVP

0.47

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.67

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.67

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over