rs2297644

chr10-97599982-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_138413.4(HOGA1):c.604-85T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,485,160 control chromosomes in the GnomAD database, including 19,382 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (1852 hom., cov: 32)
  • Exomes 𝑓: 0.16 (17530 hom.)
• Consequence: HOGA1 NM_138413.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.26

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-97599982-T-C is Benign according to our data. Variant chr10-97599982-T-C is described in ClinVar as [Benign]. Clinvar id is 1234774.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-97599982-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOGA1	NM_138413.4	c.604-85T>C		intron_variant		ENST00000370646.9
HOGA1	NM_001134670.2	c.212-1875T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOGA1	ENST00000370646.9	c.604-85T>C		intron_variant		1	NM_138413.4	P1
HOGA1	ENST00000370647.8	c.212-1875T>C		intron_variant		1
HOGA1	ENST00000370642.4	c.14-85T>C		intron_variant		5
HOGA1	ENST00000465608.1	n.1615T>C		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22854 AN: 152038 Hom.: 1851 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0922

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.0537

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.122

GnomAD4 exome AF: 0.156 AC: 208212 AN: 1333004 Hom.: 17530 Cov.: 21 AF XY: 0.155 AC XY: 103693 AN XY: 670016

Gnomad4 AFR exome AF: 0.149

Gnomad4 AMR exome AF: 0.0671

Gnomad4 ASJ exome AF: 0.121

Gnomad4 EAS exome AF: 0.0544

Gnomad4 SAS exome AF: 0.107

Gnomad4 FIN exome AF: 0.188

Gnomad4 NFE exome AF: 0.169

Gnomad4 OTH exome AF: 0.146

GnomAD4 genome AF: 0.150 AC: 22862 AN: 152156 Hom.: 1852 Cov.: 32 AF XY: 0.148 AC XY: 11025 AN XY: 74386

Gnomad4 AFR AF: 0.147

Gnomad4 AMR AF: 0.0920

Gnomad4 ASJ AF: 0.124

Gnomad4 EAS AF: 0.0538

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.185

Gnomad4 NFE AF: 0.174

Gnomad4 OTH AF: 0.123

Alfa AF: 0.163 Hom.: 2325

Bravo AF: 0.141

Asia WGS AF: 0.0890 AC: 309 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	-0.88
Cadd	Benign	1.9
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: rs2297644; hg19: chr10-99359739; COSMIC: COSV65706236;