dbSNP rs767405535: HOGA1:p.Gln116Lys (chr10-97599094-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1PM2PP2BP4_Moderate

The NM_138413.4(HOGA1):c.346C>A(p.Gln116Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

HOGA1
NM_138413.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.22

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.2157852).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOGA1	NM_138413.4 link	c.346C>A	p.Gln116Lys	missense_variant	Exon 3 of 7	ENST00000370646.9	NP_612422.2
HOGA1	NM_001134670.2 link	c.212-2763C>A		intron_variant	Intron 1 of 2		NP_001128142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
HOGA1	ENST00000370646.9 link	c.346C>A	p.Gln116Lys	missense_variant	Exon 3 of 7	1	NM_138413.4	ENSP00000359680.4
ENSG00000249967	ENST00000370649.3 link	c.212-2763C>A		intron_variant	Intron 1 of 9	2		ENSP00000359683.3
HOGA1	ENST00000370647.8 link	c.212-2763C>A		intron_variant	Intron 1 of 2	1		ENSP00000359681.4
HOGA1	ENST00000465608.1 link	n.727C>A		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

249970

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000480

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Uncertain

0.018

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.30

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.22

MetaSVM

Uncertain

-0.030

MutationAssessor

Benign

-0.23

PhyloP100

4.2

PROVEAN

Benign

-0.29

REVEL

Benign

0.23

Sift

Benign

0.66

Sift4G

Benign

0.24

Vest4

0.39

ClinPred

0.23

GERP RS

4.5

Varity_R

0.62

gMVP

0.75

Mutation Taster

=67/33

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over