rs12261752

Positions:

• chr10-97611587-C-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_138413.4(HOGA1):​c.912C>A​(p.Ala304Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,613,966 control chromosomes in the GnomAD database, including 76,576 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7081 hom., cov: 33)
  • Exomes 𝑓: 0.30 (69495 hom.)
• Consequence: HOGA1 NM_138413.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: -0.248

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]

ENSG00000249967 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 10-97611587-C-A is Benign according to our data. Variant chr10-97611587-C-A is described in ClinVar as [Benign]. Clinvar id is 204264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-97611587-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOGA1	NM_138413.4	c.912C>A	p.Ala304Ala	synonymous_variant	7/7	ENST00000370646.9	NP_612422.2
HOGA1	NM_001134670.2	c.423C>A	p.Ala141Ala	synonymous_variant	3/3		NP_001128142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOGA1	ENST00000370646.9	c.912C>A	p.Ala304Ala	synonymous_variant	7/7	1	NM_138413.4	ENSP00000359680.4
HOGA1	ENST00000370647.8	c.423C>A	p.Ala141Ala	synonymous_variant	3/3	1		ENSP00000359681.4
ENSG00000249967	ENST00000370649.3	c.345+9597C>A		intron_variant		2		ENSP00000359683.3

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45792 AN: 152082 Hom.: 7064 Cov.: 33

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.376

Gnomad SAS AF: 0.395

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.302

GnomAD3 exomes AF: 0.301 AC: 75578 AN: 251064 Hom.: 11824 AF XY: 0.309 AC XY: 41884 AN XY: 135720

Gnomad AFR exome AF: 0.309

Gnomad AMR exome AF: 0.210

Gnomad ASJ exome AF: 0.349

Gnomad EAS exome AF: 0.370

Gnomad SAS exome AF: 0.397

Gnomad FIN exome AF: 0.254

Gnomad NFE exome AF: 0.295

Gnomad OTH exome AF: 0.302

GnomAD4 exome AF: 0.305 AC: 445215 AN: 1461766 Hom.: 69495 Cov.: 37 AF XY: 0.308 AC XY: 224023 AN XY: 727180

Gnomad4 AFR exome AF: 0.315

Gnomad4 AMR exome AF: 0.217

Gnomad4 ASJ exome AF: 0.350

Gnomad4 EAS exome AF: 0.418

Gnomad4 SAS exome AF: 0.397

Gnomad4 FIN exome AF: 0.255

Gnomad4 NFE exome AF: 0.297

Gnomad4 OTH exome AF: 0.320

GnomAD4 genome AF: 0.301 AC: 45842 AN: 152200 Hom.: 7081 Cov.: 33 AF XY: 0.299 AC XY: 22234 AN XY: 74404

Gnomad4 AFR AF: 0.307

Gnomad4 AMR AF: 0.257

Gnomad4 ASJ AF: 0.356

Gnomad4 EAS AF: 0.377

Gnomad4 SAS AF: 0.396

Gnomad4 FIN AF: 0.241

Gnomad4 NFE AF: 0.300

Gnomad4 OTH AF: 0.302

Alfa AF: 0.301 Hom.: 3399

Bravo AF: 0.302

Asia WGS AF: 0.403 AC: 1400 AN: 3478

EpiCase AF: 0.300

EpiControl AF: 0.291

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria type 3 Uncertain:1 Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, no assertion criteria provided	research	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 27, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2016	p.Ala304Ala in exon 7 of HOGA1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 39.9% (6581/16500) o f South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs12261752). -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	7.8
DANN	Benign	0.77

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: rs12261752; hg19: chr10-99371344; COSMIC: COSV56729407; COSMIC: COSV56729407;