10-97584810-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1PM2PP2PP5BP4

The NM_138413.4(HOGA1):c.107C>T(p.Ala36Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,613,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A36T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

HOGA1
NM_138413.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 2.67

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

primary hyperoxaluria type 3
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)

HOGA1 links:

ENSG00000249967 (HGNC:):

ENSG00000249967 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_138413.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: -0.2785 (below the threshold of 3.09). Trascript score misZ: 0.68417 (below the threshold of 3.09). GenCC associations: The gene is linked to primary hyperoxaluria type 3.

PP5

Variant 10-97584810-C-T is Pathogenic according to our data. Variant chr10-97584810-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 204265.

BP4

Computational evidence support a benign effect (MetaRNN=0.026173383). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOGA1	NM_138413.4 link	c.107C>T	p.Ala36Val	missense_variant	Exon 1 of 7	ENST00000370646.9	NP_612422.2
HOGA1	NM_001134670.2 link	c.107C>T	p.Ala36Val	missense_variant	Exon 1 of 3		NP_001128142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
HOGA1	ENST00000370646.9 link	c.107C>T	p.Ala36Val	missense_variant	Exon 1 of 7	1	NM_138413.4	ENSP00000359680.4
ENSG00000249967	ENST00000370649.3 link	c.107C>T	p.Ala36Val	missense_variant	Exon 1 of 10	2		ENSP00000359683.3
HOGA1	ENST00000370647.8 link	c.107C>T	p.Ala36Val	missense_variant	Exon 1 of 3	1		ENSP00000359681.4
HOGA1	ENST00000465608.1 link	n.488C>T		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000172

AC:

AN:

249960

AF XY:

0.000200

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00278

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000712

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000103

AC:

151

AN:

1461498

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

727088

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00318

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000369

AC:

AN:

1111682

Other (OTH)

AF:

0.000248

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000145

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41436

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000411

Hom.:

Bravo

AF:

0.000174

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary hyperoxaluria type 3

Pathogenic:5Uncertain:1

May 30, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HOGA1 c.107C>T (p.Ala36Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 249960 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in HOGA1 causing Primary Hyperoxaluria, Type III (0.00017 vs 0.0015), allowing no conclusion about variant significance. c.107C>T has been reported in the literature in multiple compound heterozygous individuals affected with Primary Hyperoxaluria, Type III (examples: Williams_2012, Williams_2015, Pitt_2015, Bar_2021). These data indicate that the variant is likely to be associated with disease. One publication reported that the excretion of 4-Hydroxyglutamate (the metabolic precursor of the HOGA1 substrate) was elevated in Primary Hyperoxaluria, Type III patients; this cohort included at least one of the reported affected individuals who was carrying the variant of interest, though no patient specific data were provided (Pitt_2015). The following publications have been ascertained in the context of this evaluation (PMID: 33350326, 31589614, 24563386, 25629080, 22391140). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) or likely pathogenic/pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The HOGA1 c.107C>T (p.Ala36Val) missense variant has been reported in three studies in which it is found in at least three patients with primary hyperoxaluria type III (PH3) in a compound heterozygous state and in a heterozygous state in one additional patient who also carried a heterozygous deletion in the AGXT gene, which is associated with PH1 (Williams et al. 2012; Pitt et al. 2014; Williams et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00024 in the European (non-Finnish) population of the Exome Aggregation Consortium. Analysis of levels of the metabolic precursor of the HOGA1 substrate revealed that PH3 patients had significantly higher levels compared to age-matched controls, and that parental carriers showed moderate but significant increases in levels (Pitt et al. 2014). Based on the evidence, the p.Ala36Val variant is classified as likely pathogenic for primary hyperoxaluria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Jan 04, 2022

Myriad Genetics, Inc.

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_138413.3(HOGA1):c.107C>T(A36V) is a missense variant classified as a variant of uncertain significance in the context of primary hyperoxaluria type 3. A36V has been observed in cases with relevant disease (PMID: 22391140, 24563386, 33350326). Functional assessments of this variant are not available in the literature. A36V has been observed in population frequency databases (gnomAD: ASJ 0.29%). In summary, there is insufficient evidence to classify NM_138413.3(HOGA1):c.107C>T(A36V) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Oct 31, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jan 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 27, 2023

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Biochemical confirmation. ACMG: PS3 PM2 PM3 PP4 -

not provided

Pathogenic:1

Apr 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 36 of the HOGA1 protein (p.Ala36Val). This variant is present in population databases (rs201803986, gnomAD 0.3%). This missense change has been observed in individual(s) with HOGA1-related conditions (PMID: 22391140, 24563386; Invitae). 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: 204265). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HOGA1 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Uncertain

0.060

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

.;D;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.17

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.026

T;T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

0.73

N;N;.

PhyloP100

2.7

PROVEAN

Benign

-0.42

N;N;N

REVEL

Uncertain

0.48

Sift

Benign

0.038

D;T;D

Sift4G

Benign

0.064

T;T;D

Polyphen

0.30

B;B;.

Vest4

0.26

MVP

0.69

MPC

0.080

ClinPred

0.61

GERP RS

4.0

PromoterAI

-0.025

Neutral

(source)

Varity_R

0.24

gMVP

0.56

Mutation Taster

=18/82

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over