rs11817730

Positions:

• chr10-97598754-A-G

Variant summary

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

The ENST00000370646.9(HOGA1):​c.212-21A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,613,546 control chromosomes in the GnomAD database, including 31,362 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.20 (3050 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28312 hom.)
• Consequence: HOGA1 ENST00000370646.9 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: -1.86

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: This place is a probable branch point but likely benign (scored 3 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 10-97598754-A-G is Benign according to our data. Variant chr10-97598754-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 204254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOGA1	NM_138413.4	c.212-21A>G		intron_variant		ENST00000370646.9	NP_612422.2
HOGA1	NM_001134670.2	c.212-3103A>G		intron_variant			NP_001128142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOGA1	ENST00000370646.9	c.212-21A>G		intron_variant		1	NM_138413.4	ENSP00000359680	P1
HOGA1	ENST00000370647.8	c.212-3103A>G		intron_variant		1		ENSP00000359681
HOGA1	ENST00000465608.1	n.593-21A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29882 AN: 152074 Hom.: 3045 Cov.: 32

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.183

GnomAD3 exomes AF: 0.185 AC: 46483 AN: 251460 Hom.: 4437 AF XY: 0.184 AC XY: 25015 AN XY: 135906

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.162

Gnomad EAS exome AF: 0.140

Gnomad SAS exome AF: 0.185

Gnomad FIN exome AF: 0.204

Gnomad NFE exome AF: 0.197

Gnomad OTH exome AF: 0.173

GnomAD4 exome AF: 0.195 AC: 284464 AN: 1461354 Hom.: 28312 Cov.: 34 AF XY: 0.194 AC XY: 141039 AN XY: 726992

Gnomad4 AFR exome AF: 0.203

Gnomad4 AMR exome AF: 0.159

Gnomad4 ASJ exome AF: 0.167

Gnomad4 EAS exome AF: 0.115

Gnomad4 SAS exome AF: 0.184

Gnomad4 FIN exome AF: 0.203

Gnomad4 NFE exome AF: 0.200

Gnomad4 OTH exome AF: 0.193

GnomAD4 genome AF: 0.197 AC: 29917 AN: 152192 Hom.: 3050 Cov.: 32 AF XY: 0.195 AC XY: 14542 AN XY: 74406

Gnomad4 AFR AF: 0.202

Gnomad4 AMR AF: 0.184

Gnomad4 ASJ AF: 0.171

Gnomad4 EAS AF: 0.140

Gnomad4 SAS AF: 0.181

Gnomad4 FIN AF: 0.199

Gnomad4 NFE AF: 0.204

Gnomad4 OTH AF: 0.182

Alfa AF: 0.194 Hom.: 4243

Bravo AF: 0.194

Asia WGS AF: 0.162 AC: 560 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria type 3 Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	research	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 27, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	-0.93
CADD	Benign	0.20
DANN	Benign	0.20
La Branchor		0.76
BranchPoint Hunter		3.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs11817730; hg19: chr10-99358511; COSMIC: COSV65706328; COSMIC: COSV65706328;