Genetic Variant NM_012203.2:c.2T>G (chr9-37422752-T-G) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_012203.2(GRHPR):c.2T>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000028 in 1,431,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

GRHPR
NM_012203.2 start_lost

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.11

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: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Ambry Genetics

GRHPR links:

ENSG00000294170 (HGNC:):

ENSG00000294170 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 4 pathogenic variants. Next in-frame start position is after 7 codons. Genomic position: 37422769. Lost 0.019 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-37422752-T-G is Pathogenic according to our data. Variant chr9-37422752-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 551406.Status of the report is no_assertion_criteria_provided, 0 stars.

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.2T>G	p.Met1?	start_lost	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.2T>G	p.Met1?	start_lost	Exon 1 of 9	ENSP00000313432.6	Q9UBQ7-1
GRHPR	ENST00000460882.5	TSL:1	n.57T>G		non_coding_transcript_exon	Exon 1 of 9
GRHPR	ENST00000493368.5	TSL:1	n.87T>G		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000280

AC:

AN:

1431034

Hom.:

Cov.:

AF XY:

0.00000564

AC XY:

AN XY:

709488

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32602

American (AMR)

AF:

0.00

AC:

AN:

41396

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25666

East Asian (EAS)

AF:

0.00

AC:

AN:

37540

South Asian (SAS)

AF:

0.00

AC:

AN:

82136

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50046

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4260

European-Non Finnish (NFE)

AF:

0.00000364

AC:

AN:

1098346

Other (OTH)

AF:

0.00

AC:

AN:

59042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

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

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary hyperoxaluria, type II (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.015

Eigen

Benign

-0.099

Eigen_PC

Benign

-0.092

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

-0.21

PhyloP100

3.1

PROVEAN

Benign

-1.0

REVEL

Uncertain

0.57

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Polyphen

0.36

Vest4

0.84

MutPred

0.97

Gain of methylation at M1 (P = 0.0335)

MVP

0.89

ClinPred

0.96

GERP RS

4.8

PromoterAI

0.026

Neutral

(source)

Varity_R

0.97

gMVP

0.62

Mutation Taster

=64/136

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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