Genetic Variant GRHPR:c.866-10_866-9delTC (chr9-37436635-CCT-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012203.2(GRHPR):c.866-10_866-9delTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00867 in 1,204,624 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0099 ( 0 hom. )

Consequence

GRHPR
NM_012203.2 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0240

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

GRHPR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Variant has high frequency in the EAS (0.0297) population. However there is too low homozygotes in high coverage region: (expected more than 22, got 0).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRHPR	NM_012203.2 link	c.866-10_866-9delTC		intron_variant	Intron 8 of 8	ENST00000318158.11	NP_036335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRHPR	ENST00000318158.11 link	c.866-25_866-24delCT		intron_variant	Intron 8 of 8	1	NM_012203.2	ENSP00000313432.6

Frequencies

GnomAD3 genomes

AF:

0.000265

AC:

AN:

150870

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000396

Gnomad ASJ

AF:

0.00376

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000626

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000163

Gnomad OTH

AF:

0.000484

GnomAD2 exomes

AF:

0.00717

AC:

768

AN:

107182

AF XY:

0.00705

show subpopulations

Gnomad AFR exome

AF:

0.00377

Gnomad AMR exome

AF:

0.00475

Gnomad ASJ exome

AF:

0.0102

Gnomad EAS exome

AF:

0.0126

Gnomad FIN exome

AF:

0.0166

Gnomad NFE exome

AF:

0.00543

Gnomad OTH exome

AF:

0.00535

GnomAD4 exome

AF:

0.00987

AC:

10403

AN:

1053652

Hom.:

AF XY:

0.00961

AC XY:

4957

AN XY:

516064

show subpopulations

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

African (AFR)

AF:

0.0126

AC:

280

AN:

22142

American (AMR)

AF:

0.0124

AC:

267

AN:

21578

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

295

AN:

18916

East Asian (EAS)

AF:

0.0318

AC:

618

AN:

19424

South Asian (SAS)

AF:

0.00705

AC:

325

AN:

46102

European-Finnish (FIN)

AF:

0.0159

AC:

582

AN:

36650

Middle Eastern (MID)

AF:

0.00710

AC:

AN:

4650

European-Non Finnish (NFE)

AF:

0.00889

AC:

7479

AN:

841036

Other (OTH)

AF:

0.0121

AC:

524

AN:

43154

⚠️ 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: 0.245

Heterozygous variant carriers

1724

3448

5173

6897

8621

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

258

516

774

1032

1290

<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

AF:

0.000265

AC:

AN:

150972

Hom.:

Cov.:

AF XY:

0.000339

AC XY:

AN XY:

73710

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41250

American (AMR)

AF:

0.000395

AC:

AN:

15174

Ashkenazi Jewish (ASJ)

AF:

0.00376

AC:

AN:

3456

East Asian (EAS)

AF:

0.000194

AC:

AN:

5162

South Asian (SAS)

AF:

0.000627

AC:

AN:

4782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000163

AC:

AN:

67598

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0726

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.024

Mutation Taster

=100/0

polymorphism

(source)

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

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9-37436635-CCTCTCTCTCTCT-CCTCTCTCTCT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over