chr10-97584912-G-C

Position:

chr10-97584912-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_138413.4(HOGA1):c.209G>C(p.Arg70Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,702 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

HOGA1
NM_138413.4 missense, splice_region

Scores

Splicing: ADA: 0.002995

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 2.80

Variant links:

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 links:

ENSG00000249967 (HGNC:):

ENSG00000249967 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-97584912-G-C is Pathogenic according to our data. Variant chr10-97584912-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 33.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-97584912-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOGA1	NM_138413.4 linkuse as main transcript	c.209G>C	p.Arg70Pro	missense_variant, splice_region_variant	1/7	ENST00000370646.9	NP_612422.2	Q86XE5-1
HOGA1	NM_001134670.2 linkuse as main transcript	c.209G>C	p.Arg70Pro	missense_variant, splice_region_variant	1/3		NP_001128142.1	Q86XE5-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HOGA1	ENST00000370646.9 linkuse as main transcript	c.209G>C	p.Arg70Pro	missense_variant, splice_region_variant	1/7	1	NM_138413.4	ENSP00000359680.4	Q86XE5-1
ENSG00000249967	ENST00000370649.3 linkuse as main transcript	c.209G>C	p.Arg70Pro	missense_variant, splice_region_variant	1/10	2		ENSP00000359683.3	E9PAM4
HOGA1	ENST00000370647.8 linkuse as main transcript	c.209G>C	p.Arg70Pro	missense_variant, splice_region_variant	1/3	1		ENSP00000359681.4	Q86XE5-3
HOGA1	ENST00000465608.1 linkuse as main transcript	n.590G>C		splice_region_variant, non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461500

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727070

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary hyperoxaluria type 3

Pathogenic:2

Pathogenic, no assertion criteria provided	in vitro	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 27, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 10, 2010	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 25, 2023

This missense change has been observed in individual(s) with primary hyperoxaluria type 3 (PMID: 20797690, 22781098, 28711958). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HOGA1 function (PMID: 22771891). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 33). This variant is present in population databases (rs267606763, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 70 of the HOGA1 protein (p.Arg70Pro). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.72

.;D;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.75

T;D;T

M_CAP

Uncertain

0.26

MetaRNN

Uncertain

0.67

D;D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Uncertain

2.6

M;M;.

PROVEAN

Benign

-1.1

N;D;N

REVEL

Pathogenic

0.69

Sift

Benign

0.093

T;D;D

Sift4G

Pathogenic

0.0

D;T;D

Polyphen

0.96

D;P;.

Vest4

0.70

MutPred

0.54

Loss of methylation at R70 (P = 0.0055);Loss of methylation at R70 (P = 0.0055);Loss of methylation at R70 (P = 0.0055);

MVP

0.78

MPC

0.42

ClinPred

0.77

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.95

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0030

dbscSNV1_RF

Benign

0.048

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over