9-37422751-A-T

Variant names:

• chr9-37422751-A-T
• rs1554746094
• NM_012203.2:c.1A>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Supporting PM2 PP5_Moderate

The NM_012203.2(GRHPR):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRHPR NM_012203.2 initiator_codon
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.15

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. 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 9-37422751-A-T is Pathogenic according to our data. Variant chr9-37422751-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556994.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRHPR	NM_012203.2	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 9	ENST00000318158.11	NP_036335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRHPR	ENST00000318158.11	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 9	1	NM_012203.2	ENSP00000313432.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary hyperoxaluria, type II Pathogenic:1

Mar 06, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	19
DANN	Benign	0.72
DEOGEN2	Benign	0.015	T;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Benign	-0.55	T
PROVEAN	Benign	-0.99	N;.
REVEL	Uncertain	0.47
Sift	Benign	0.064	T;.
Sift4G	Uncertain	0.045	D;D
Polyphen		0.0	B;.
Vest4		0.85
MutPred		0.98		Loss of disorder (P = 0.0881);Loss of disorder (P = 0.0881);
MVP		0.75
ClinPred		0.26	T
GERP RS		2.3
Varity_R		0.64
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554746094; hg19: chr9-37422748;