rs397509360

Variant names:

• chr10-97611611-TGAG-T
• rs397509360
• NM_138413.4:c.944_946delAGG

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_138413.4(HOGA1):​c.944_946delAGG​(p.Glu315del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000251 in 1,614,020 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000245619: "In vitro functional studies suggest that this variant impacts protein function (MacDonald 2016)."" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. E315E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: HOGA1 NM_138413.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18 O:1
• Conservation: PhyloP100: 8.99
• Publications: 16 publications found

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]

HOGA1 Gene-Disease associations (from GenCC):

• primary hyperoxaluria type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000249967 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000245619: "In vitro functional studies suggest that this variant impacts protein function (MacDonald 2016)."; SCV000915489: Expression of the p.Glu315del variant protein in CHO cells revealed that the protein was mislocalized and retained no measurable activity (Riedel et al. 2012). Expression analysis in HEK293 cells demonstrated the p.Glu315del variant protein was unstable and was only detected in the presence of 26S proteasome inhibitor (MacDonald et al. 2016).; SCV001142411: Experimental studies have shown that this missense change leads to HOGA1 protein instability (PMID: 22771891; 27096395).; SCV003923285: Experimental studies have found that the variant results in a protein that is unstable, is rapidly degraded, and retains no measurable enzymatic activity in vitro (e.g.Riedel_2012, MacDonald_2016).; SCV000956272: Experimental studies have shown that this variant affects HOGA1 function (PMID: 22771891, 27096395).; SCV001784510: Published functional studies demonstrate targeted cellular degradation and an absence of HOGA1 protein (PMID: 27096395); SCV004115278: "In vitro experimental studies suggest this variant affects protein function leading to preferential degradation through the ubiquitin proteasome pathway (Riedel et al. 2012. PubMed ID: 22771891; Figure 4, MacDonald et al. 2016. PubMed ID: 27096395)."
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_138413.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_138413.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 10-97611611-TGAG-T is Pathogenic according to our data. Variant chr10-97611611-TGAG-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 29.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138413.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOGA1	NM_138413.4	MANE Select	c.944_946delAGG	p.Glu315del	disruptive_inframe_deletion	Exon 7 of 7	NP_612422.2
	HOGA1	NM_001134670.2		c.455_457delAGG	p.Glu152del	disruptive_inframe_deletion	Exon 3 of 3	NP_001128142.1	Q86XE5-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOGA1	ENST00000370646.9	TSL:1 MANE Select	c.944_946delAGG	p.Glu315del	disruptive_inframe_deletion	Exon 7 of 7	ENSP00000359680.4	Q86XE5-1
	HOGA1	ENST00000370647.8	TSL:1	c.455_457delAGG	p.Glu152del	disruptive_inframe_deletion	Exon 3 of 3	ENSP00000359681.4	Q86XE5-3
	ENSG00000249967	ENST00000370649.3	TSL:2	c.345+9629_345+9631delAGG		intron	N/A	ENSP00000359683.3	E9PAM4

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000466 AC: 117 AN: 251206 AF XY: 0.000427

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00914

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000249 AC: 364 AN: 1461798 Hom.: 1 AF XY: 0.000267 AC XY: 194 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00949 AC: 248 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000558 AC: 62 AN: 1111978

Other (OTH) AF: 0.000811 AC: 49 AN: 60394

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.000350 AC XY: 26 AN XY: 74372

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

American (AMR) AF: 0.000196 AC: 3 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00951 AC: 33 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00161 Hom.: 0

Bravo AF: 0.000332

EpiCase AF: 0.000327

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
13	-	-	Primary hyperoxaluria type 3 (14)
4	-	-	not provided (4)
1	-	-	HOGA1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.0
Mutation Taster		=43/57	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397509360; hg19: chr10-99371368;