10-97598784-T-C

Variant names:

• chr10-97598784-T-C
• rs796052084
• NM_138413.4:c.221T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP5_Moderate

The NM_138413.4(HOGA1):​c.221T>C​(p.Val74Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. V74G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HOGA1 NM_138413.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.52
• Publications: 0 publications found

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]

HOGA1 Gene-Disease associations (from GenCC):

• primary hyperoxaluria type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000249967 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_138413.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-97598784-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 204267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: -0.2785 (below the threshold of 3.09). Trascript score misZ: 0.68417 (below the threshold of 3.09). GenCC associations: The gene is linked to primary hyperoxaluria type 3.
• PP5: Variant 10-97598784-T-C is Pathogenic according to our data. Variant chr10-97598784-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2753716.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOGA1	NM_138413.4	c.221T>C	p.Val74Ala	missense_variant	Exon 2 of 7	ENST00000370646.9	NP_612422.2
HOGA1	NM_001134670.2	c.212-3073T>C		intron_variant	Intron 1 of 2		NP_001128142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOGA1	ENST00000370646.9	c.221T>C	p.Val74Ala	missense_variant	Exon 2 of 7	1	NM_138413.4	ENSP00000359680.4
ENSG00000249967	ENST00000370649.3	c.212-3073T>C		intron_variant	Intron 1 of 9	2		ENSP00000359683.3
HOGA1	ENST00000370647.8	c.212-3073T>C		intron_variant	Intron 1 of 2	1		ENSP00000359681.4
HOGA1	ENST00000465608.1	n.602T>C		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Aug 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 74 of the HOGA1 protein (p.Val74Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HOGA1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HOGA1 protein function. This variant disrupts the p.Val74 amino acid residue in HOGA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22781098, 28711958). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.5
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.81
Sift	Benign	0.059	T
Sift4G	Uncertain	0.017	D
Polyphen		0.32	B
Vest4		0.55
MutPred		0.65		Gain of disorder (P = 0.1154);
MVP		0.79
MPC		0.43
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.62
gMVP		0.81
Mutation Taster		=25/75	disease causing

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: rs796052084; hg19: chr10-99358541;