rs11817730

Variant names:

• chr10-97598754-A-G
• rs11817730
• NM_138413.4:c.212-21A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138413.4(HOGA1):​c.212-21A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,613,546 control chromosomes in the GnomAD database, including 31,362 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.20 (3050 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28312 hom.)
• Consequence: HOGA1 NM_138413.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: -1.86
• Publications: 18 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: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000249967 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 10-97598754-A-G is Benign according to our data. Variant chr10-97598754-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 204254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOGA1	NM_138413.4	MANE Select	c.212-21A>G		intron	N/A	NP_612422.2
	HOGA1	NM_001134670.2		c.212-3103A>G		intron	N/A	NP_001128142.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOGA1	ENST00000370646.9	TSL:1 MANE Select	c.212-21A>G		intron	N/A	ENSP00000359680.4
	ENSG00000249967	ENST00000370649.3	TSL:2	c.212-3103A>G		intron	N/A	ENSP00000359683.3
	HOGA1	ENST00000370647.8	TSL:1	c.212-3103A>G		intron	N/A	ENSP00000359681.4

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29882 AN: 152074 Hom.: 3045 Cov.: 32

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.183

GnomAD2 exomes AF: 0.185 AC: 46483 AN: 251460 AF XY: 0.184

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.162

Gnomad EAS exome AF: 0.140

Gnomad FIN exome AF: 0.204

Gnomad NFE exome AF: 0.197

Gnomad OTH exome AF: 0.173

GnomAD4 exome AF: 0.195 AC: 284464 AN: 1461354 Hom.: 28312 Cov.: 34 AF XY: 0.194 AC XY: 141039 AN XY: 726992

African (AFR) AF: 0.203 AC: 6809 AN: 33474

American (AMR) AF: 0.159 AC: 7123 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 4376 AN: 26134

East Asian (EAS) AF: 0.115 AC: 4583 AN: 39696

South Asian (SAS) AF: 0.184 AC: 15850 AN: 86248

European-Finnish (FIN) AF: 0.203 AC: 10833 AN: 53414

Middle Eastern (MID) AF: 0.169 AC: 973 AN: 5764

European-Non Finnish (NFE) AF: 0.200 AC: 222269 AN: 1111530

Other (OTH) AF: 0.193 AC: 11648 AN: 60372

GnomAD4 genome AF: 0.197 AC: 29917 AN: 152192 Hom.: 3050 Cov.: 32 AF XY: 0.195 AC XY: 14542 AN XY: 74406

African (AFR) AF: 0.202 AC: 8372 AN: 41528

American (AMR) AF: 0.184 AC: 2808 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 593 AN: 3466

East Asian (EAS) AF: 0.140 AC: 725 AN: 5182

South Asian (SAS) AF: 0.181 AC: 871 AN: 4818

European-Finnish (FIN) AF: 0.199 AC: 2103 AN: 10588

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.204 AC: 13871 AN: 68000

Other (OTH) AF: 0.182 AC: 384 AN: 2108

Alfa AF: 0.195 Hom.: 5787

Bravo AF: 0.194

Asia WGS AF: 0.162 AC: 560 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	1	Primary hyperoxaluria type 3 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.20
DANN	Benign	0.20
PhyloP100		-1.9
La Branchor		0.76
BranchPoint Hunter		3.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs11817730; hg19: chr10-99358511; COSMIC: COSV65706328; COSMIC: COSV65706328;