10-97584767-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138413.4(HOGA1):c.64G>A(p.Val22Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V22V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HOGA1 NM_138413.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.855

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053811908).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOGA1	NM_138413.4	c.64G>A	p.Val22Met	missense_variant	1/7	ENST00000370646.9
HOGA1	NM_001134670.2	c.64G>A	p.Val22Met	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOGA1	ENST00000370646.9	c.64G>A	p.Val22Met	missense_variant	1/7	1	NM_138413.4	P1
HOGA1	ENST00000370647.8	c.64G>A	p.Val22Met	missense_variant	1/3	1
HOGA1	ENST00000465608.1	n.445G>A		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250634 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135440

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461290 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726862

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Primary hyperoxaluria type 3 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 27, 2020

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2019

This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with methionine at codon 22 of the HOGA1 protein (p.Val22Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant has not been reported in the literature in individuals with HOGA1-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	0.49
Dann	Benign	0.89
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.054	T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.55	N;N;.
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-0.86	N;N;N
REVEL	Benign	0.060
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.0020	B;B;.
Vest4		0.030
MutPred		0.20		Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);
MVP		0.43
MPC		0.068
ClinPred		0.036	T
GERP RS		-1.8
Varity_R		0.040
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1425518232; hg19: chr10-99344524;