rs779492256

chr10-97600097-A-Cchr10-97600097-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

The NM_138413.4(HOGA1):c.634A>C(p.Thr212Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,888 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T212A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HOGA1 NM_138413.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.27

Genes affected

HOGA1 (HGNC:25155): (4-hydroxy-2-oxoglutarate aldolase 1) The authors of PMID:20797690 cloned this gene while searching for genes in a region of chromosome 10 linked to primary hyperoxalurea type III. They noted that even though the encoded protein has been described as a mitochondrial dihydrodipicolinate synthase-like enzyme, it shares little homology with E. coli dihydrodipicolinate synthase (Dhdps), particularly in the putative substrate-binding region. Moreover, neither lysine biosynthesis nor sialic acid metabolism, for which Dhdps is responsible, occurs in vertebrate mitochondria. They propose that this gene encodes mitochondrial 4-hydroxyl-2-oxoglutarate aldolase (EC 4.1.3.16), which catalyzes the final step in the metabolic pathway of hydroxyproline, releasing glyoxylate and pyruvate. This gene is predominantly expressed in the liver and kidney, and mutations in this gene are found in patients with primary hyperoxalurea type III. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-97600097-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 556110.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902
• PP5: Variant 10-97600097-A-C is Pathogenic according to our data. Variant chr10-97600097-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2664395.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOGA1	NM_138413.4	c.634A>C	p.Thr212Pro	missense_variant	5/7	ENST00000370646.9
HOGA1	NM_001134670.2	c.212-1760A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOGA1	ENST00000370646.9	c.634A>C	p.Thr212Pro	missense_variant	5/7	1	NM_138413.4	P1
HOGA1	ENST00000370647.8	c.212-1760A>C		intron_variant		1
HOGA1	ENST00000370642.4	c.46A>C	p.Thr16Pro	missense_variant	2/4	5
HOGA1	ENST00000465608.1	n.1730A>C		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary hyperoxaluria type 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Clinical Biochemistry Laboratory, Health Services Laboratory

Oct 27, 2023

ACMG:PM3 PM5 PP3 PP3 BP1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.69		Loss of MoRF binding (P = 0.0658);
MVP		0.84
MPC		0.46
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.99
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs779492256; hg19: chr10-99359854;