9-37436635-CCTCTCTCTCTCT-CCTCTCTCTCT

Variant names:

• chr9-37436635-CCT-C
• rs34302950
• NM_012203.2:c.866-10_866-9delTC

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0240
• Publications: 0 publications found

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)

ACMG classification

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).

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.866-10_866-9delTC		intron	N/A	NP_036335.1	A0A384N605

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHPR	ENST00000318158.11	TSL:1 MANE Select	c.866-25_866-24delCT		intron	N/A	ENSP00000313432.6	Q9UBQ7-1
	GRHPR	ENST00000460882.5	TSL:1	n.893-25_893-24delCT		intron	N/A
	GRHPR	ENST00000874646.1		c.974-25_974-24delCT		intron	N/A	ENSP00000544705.1

Frequencies

GnomAD3 genomes AF: 0.000265 AC: 40 AN: 150870 Hom.: 0 Cov.: 28

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

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.: 0 AF XY: 0.00961 AC XY: 4957 AN XY: 516064

⚠️ 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: 33 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.

GnomAD4 genome AF: 0.000265 AC: 40 AN: 150972 Hom.: 0 Cov.: 28 AF XY: 0.000339 AC XY: 25 AN XY: 73710

African (AFR) AF: 0.000121 AC: 5 AN: 41250

American (AMR) AF: 0.000395 AC: 6 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.00376 AC: 13 AN: 3456

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.000627 AC: 3 AN: 4782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000163 AC: 11 AN: 67598

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.0726 Hom.: 82

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.024
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs34302950; hg19: chr9-37436632;