rs185803104

Positions:

• chr10-97600168-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The NM_138413.4(HOGA1):​c.700+5G>T variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,611,160 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (4 hom.)
• Consequence: HOGA1 NM_138413.4 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 8.63

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 Pathogenic. Variant got 12 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 10-97600168-G-T is Pathogenic according to our data. Variant chr10-97600168-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 204285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOGA1	NM_138413.4	c.700+5G>T		splice_donor_5th_base_variant, intron_variant		ENST00000370646.9	NP_612422.2
HOGA1	NM_001134670.2	c.212-1689G>T		intron_variant			NP_001128142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOGA1	ENST00000370646.9	c.700+5G>T		splice_donor_5th_base_variant, intron_variant		1	NM_138413.4	ENSP00000359680	P1
HOGA1	ENST00000370647.8	c.212-1689G>T		intron_variant		1		ENSP00000359681
HOGA1	ENST00000370642.4	c.110+5G>T		splice_donor_5th_base_variant, intron_variant		5		ENSP00000359676
HOGA1	ENST00000465608.1	n.1801G>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00151 AC: 230 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00253

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00124 AC: 312 AN: 251412 Hom.: 1 AF XY: 0.00123 AC XY: 167 AN XY: 135876

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00210

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00234 AC: 3420 AN: 1458922 Hom.: 4 Cov.: 30 AF XY: 0.00229 AC XY: 1660 AN XY: 726036

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000599

Gnomad4 NFE exome AF: 0.00288

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00151 AC: 230 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.00137 AC XY: 102 AN XY: 74438

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00253

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00189 Hom.: 0

Bravo AF: 0.00159

EpiCase AF: 0.00251

EpiControl AF: 0.00202

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria type 3 Pathogenic:8 Other:1

Pathogenic, no assertion criteria provided	research	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 27, 2014	Abnormally spliced hepatic RNA (PMID:22391140) -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 16, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with primary hyperoxaluria type III (MIM#613616). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity with regard to phenotype severity and age of onset (PMID: 25644115). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. This variant has been shown by RNA studies to result in the use of a cryptic splice site, which is predicted to result in an inframe insertion of 17 amino acids (PMID: 21896830, 22391140). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (335 heterozygotes, 1 homozygote). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is the most common primary hyperoxaluria type III-associated variant in European populations (ClinVar; PMID: 21896830, 22391140, 25644115). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 17, 2019	NM_138413.3(HOGA1):c.700+5G>T is classified as pathogenic in the context of primary hyperoxaluria type 3. Sources cited for classification include the following: PMID 22781098, 22391140, 21896830 and 20797690. Classification of NM_138413.3(HOGA1):c.700+5G>T is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 28, 2022	Variant summary: HOGA1 c.700+5G>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Indeed, it has been demonstrated that the variant weakens the wild-type 5' donor splice site resulting instead in the activation of a downstream cryptic splice site which produces an in-frame insertion of 51 nucleotides (17 codons) from intron 5 (e.g. Monico_2011, Williams_2012).The variant allele was found at a frequency of 0.0012 in 251412 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in HOGA1 causing Primary Hyperoxaluria, Type III (0.0012 vs 0.0015). c.700+5G>T has been reported in the literature in many homozygous and compound heterozygous individuals affected with Primary Hyperoxaluria, Type III, predominantly of European ancestry (e.g. Belostotsky_2010, Monico_2011, Williams_2012, Beck_2013, Williams_2015). It is described as a common pathogenic variant in HOGA1, having been reported at allele frequencies of 47-67% in patients with Primary Hyperoxaluria, Type III and it has been suggeted that it represents a founder variant in the northern European population (Williams_2012, Beck_2013). These data indicate that the variant is very likely to be associated with disease. Ten assessments for this variant have been submitted to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 05, 2016	The c.700+5G>T variant in HOGA1 is one of the most common HOGA1 pathogenic varia nts in patients with primary hyperoxaluria type 3 (Belostosky 2010, Williams 201 2). This variant has been identified in 0.2% (247/126672) of European chromosome s by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs185803104). Although this variant has been seen in the general populati on, its frequency is low enough to be consistent with a recessive carrier freque ncy. This variant is located in the 5' splice region and was demonstrated to lea d to altered splicing and in-frame insertion of 52 nucleotides in patient cells (Monico 2011, Williams 2012). In summary, this variant meets our criteria to be classified as pathogenic for primary hyperoxaluria type 3 in an autosomal recess ive manner. ACMG/AMP Criteria applied: PM3_VeryStrong; PM2; PM4. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 07, 2018	The HOGA1 c.700+5G>T splice_region variant has been reported in at least six studies in which it is found in at least 36 patients with primary hyperoxaluria, including in 24 in a homozygous state and in 12 in a compound heterozygous state (Belostotsky et al. 2010; Monico et al. 2011; Williams et al. 2012; Beck et al. 2013; Hopp et al. 2015). This variant is described as the most common pathogenic variant in the HOGA1 gene, being identified in 67% of disease alleles (Hoppe et al. 2012). The c.700+5G>T variant was absent from 113 controls, but is reported at a frequency of 0.00302 in the European American population of the Exome Aggregation Consortium. Williams et al. (2012) utilized RNA from a patient who was homozygous for the c.700+5G>T variant to demonstrate that there was activation of a cryptic splice site via an inframe insertion of 51 nucleotides and 17 amino acids. Based on the collective evidence, the c.700+5G>T variant is classified as pathogenic for primary hyperoxaluria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 23, 2019	PS4, PS3, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change falls in intron 5 of the HOGA1 gene. It does not directly change the encoded amino acid sequence of the HOGA1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 17 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs185803104, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with HOGA1-related primary hyperoxaluria type 3 (PMID: 22391140, 22781098, 24563386, 25644115). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 204285). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site in intron 5 (PMID: 21896830). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2021	Published functional studies demonstrate the variant results in an in-frame insertion of 51bp due to weakening of the natural splice site and use of a downstream cryptic splice site (Monico et al., 2011; Williams et al., 2012; Beck et al., 2013); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22391140, 25644115, 30609409, 21896830, 24563386, 20797690, 22781098, 27096395, 26401545, 22851625, 26340091, 25629080, 25972204, 28711958, 27838384, 31980526, 34426522, 31589614, 33226606) -

HOGA1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 05, 2023

The HOGA1 c.700+5G>T variant is predicted to interfere with splicing. This variant has been reported to be pathogenic for primary hyperoxaluria (Hopp et al. 2015. PubMed ID: 25644115; Beck et al. 2013. PubMed ID: 22781098; reported as c.701+4G>T in Belostotsky et al. 2010. PubMed ID: 20797690). This variant is reported in 0.20% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In summary, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.28		Position offset: 46
DS_DL_spliceai		0.64		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs185803104; hg19: chr10-99359925;