10-97584425-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138413.4(HOGA1):c.-279G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0273 in 418,560 control chromosomes in the GnomAD database, including 284 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (110 hom., cov: 32)
  • Exomes 𝑓: 0.027 (174 hom.)
• Consequence: HOGA1 NM_138413.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0960

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 10-97584425-G-A is Benign according to our data. Variant chr10-97584425-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 301787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0771 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOGA1	NM_138413.4	c.-279G>A		5_prime_UTR_variant	1/7	ENST00000370646.9
HOGA1	NM_001134670.2	c.-279G>A		5_prime_UTR_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOGA1	ENST00000370646.9	c.-279G>A		5_prime_UTR_variant	1/7	1	NM_138413.4	P1
HOGA1	ENST00000370647.8	c.-279G>A		5_prime_UTR_variant	1/3	1
HOGA1	ENST00000465608.1	n.103G>A		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.0278 AC: 4225 AN: 152192 Hom.: 106 Cov.: 32

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0798

Gnomad ASJ AF: 0.0328

Gnomad EAS AF: 0.0834

Gnomad SAS AF: 0.0693

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0197

Gnomad OTH AF: 0.0440

GnomAD4 exome AF: 0.0270 AC: 7182 AN: 266250 Hom.: 174 Cov.: 0 AF XY: 0.0281 AC XY: 3799 AN XY: 135240

Gnomad4 AFR exome AF: 0.0143

Gnomad4 AMR exome AF: 0.0798

Gnomad4 ASJ exome AF: 0.0339

Gnomad4 EAS exome AF: 0.0487

Gnomad4 SAS exome AF: 0.0582

Gnomad4 FIN exome AF: 0.0122

Gnomad4 NFE exome AF: 0.0199

Gnomad4 OTH exome AF: 0.0316

GnomAD4 genome AF: 0.0278 AC: 4237 AN: 152310 Hom.: 110 Cov.: 32 AF XY: 0.0292 AC XY: 2174 AN XY: 74500

Gnomad4 AFR AF: 0.0130

Gnomad4 AMR AF: 0.0805

Gnomad4 ASJ AF: 0.0328

Gnomad4 EAS AF: 0.0836

Gnomad4 SAS AF: 0.0692

Gnomad4 FIN AF: 0.0114

Gnomad4 NFE AF: 0.0197

Gnomad4 OTH AF: 0.0435

Alfa AF: 0.0221 Hom.: 10

Bravo AF: 0.0316

Asia WGS AF: 0.0630 AC: 218 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	1.7
Dann	Benign	0.46

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: rs41309988; hg19: chr10-99344182;