NM_012203.2:c.866-14_866-9dupTCTCTC

Variant names:

• chr9-37436635-C-CCTCTCT
• rs34302950
• NM_012203.2:c.866-14_866-9dupTCTCTC

Variant summary

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

The NM_012203.2(GRHPR):​c.866-14_866-9dupTCTCTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,374,110 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: not found (cov: 28)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: GRHPR NM_012203.2 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.689
• 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, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet

ACMG classification

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

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

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHPR	NM_012203.2	MANE Select	c.866-14_866-9dupTCTCTC		splice_region intron	N/A	NP_036335.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHPR	ENST00000318158.11	TSL:1 MANE Select	c.866-26_866-25insCTCTCT		intron	N/A	ENSP00000313432.6
	GRHPR	ENST00000460882.5	TSL:1	n.893-26_893-25insCTCTCT		intron	N/A
	GRHPR	ENST00000480596.5	TSL:2	n.1567-26_1567-25insCTCTCT		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.0000124 AC: 17 AN: 1374110 Hom.: 0 Cov.: 29 AF XY: 0.0000132 AC XY: 9 AN XY: 684098

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

African (AFR) AF: 0.0000318 AC: 1 AN: 31460

American (AMR) AF: 0.00 AC: 0 AN: 41988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24672

East Asian (EAS) AF: 0.00 AC: 0 AN: 36556

South Asian (SAS) AF: 0.00 AC: 0 AN: 81088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5512

European-Non Finnish (NFE) AF: 0.0000143 AC: 15 AN: 1045846

Other (OTH) AF: 0.0000176 AC: 1 AN: 56730

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000035519), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

Alfa AF: 0.0000417 Hom.: 82

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.69

Splicing

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

Other links and lift over

dbSNP: rs34302950; hg19: chr9-37436632;