rs120074173

chr3-120633233-T-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_000187.4(HGD):c.1102A>G(p.Met368Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,614,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: HGD NM_000187.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 7.46

Genes affected

HGD (HGNC:4892): (homogentisate 1,2-dioxygenase) This gene encodes the enzyme homogentisate 1,2 dioxygenase. This enzyme is involved in the catabolism of the amino acids tyrosine and phenylalanine. Mutations in this gene are the cause of the autosomal recessive metabolism disorder alkaptonuria.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000187.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.83
• PP5: Variant 3-120633233-T-C is Pathogenic according to our data. Variant chr3-120633233-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 3173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-120633233-T-C is described in Lovd as [Likely_pathogenic]. Variant chr3-120633233-T-C is described in Lovd as [Pathogenic]. Variant chr3-120633233-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HGD	NM_000187.4	c.1102A>G	p.Met368Val	missense_variant	13/14	ENST00000283871.10
HGD	XM_005247412.3	c.877A>G	p.Met293Val	missense_variant	11/12
HGD	XM_017006277.3	c.679A>G	p.Met227Val	missense_variant	13/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HGD	ENST00000283871.10	c.1102A>G	p.Met368Val	missense_variant	13/14	1	NM_000187.4	P1
HGD	ENST00000470321.1	n.442A>G		non_coding_transcript_exon_variant	3/3	3
HGD	ENST00000492108.5	c.*84A>G		3_prime_UTR_variant, NMD_transcript_variant	5/6	2

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152134 Hom.: 0 Cov.: 32

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: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000167 AC: 42 AN: 251288 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135798

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000335

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000196 AC: 287 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.000195 AC XY: 142 AN XY: 727240

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000236

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74454

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: 0.000188

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000392 Hom.: 0

Bravo AF: 0.000246

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000545

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alkaptonuria Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 23, 2018	Across a selection of the available literature, the HGD c.1102A>G (p.Met368Val) missense variant has been identified in 42 individuals with alkaptonuria, including in a homozygous state in eight individuals, in a compound heterozygous state in 32 individuals, and in a heterozygous state in three individuals (Beltrán-Valero de Bernabé et al. 1998; Beltrán-Valero de Bernabé et al. 1999a; Beltrán-Valero de Bernabé et al. 1999b; Felbor et al. 1999; Vilboux et al. 2009; Zatkova et al. 2012). The p.Met368Val variant was absent from at least 78 controls and is reported at a frequency of 0.00037 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Met368Val variant is classified as pathogenic for alkaptonuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 18, 2015	- -
Pathogenic, no assertion criteria provided	research	Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	-	The variant was originally described in AKU patient in PMID:9529363. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00097). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1999	- -
not provided, no classification provided	literature only	GeneReviews	-	Most prevalent pathogenic variant in Europe (excluding the Slovak population) -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Aug 25, 2015	The c.1102A>G, p.Met368Val variant was observed to segregate with the disease in multiple affected families [Beltrán-Valero de Bernabé D et al., (1998); Vilboux T et al., (2009)]. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls [Vilboux T et al., (2009)]. The M368 residue is close to the active site of the enzyme and is located in a domain called the RmlC-like jelly roll fold. Furthermore, in an enzyme kinetics assay, this variant showed decreased activity (37% of the wild-type), reduced catalytic efficiency (14% of wild-type) and disrupted hydrophobic contacts between subunits in the trimeric assembly [Rodríguez JM et al., (2000)]. Several computational algorithms predicted a damaging effect of this variant on the protein. The frequency of this variant is below the disease-allele frequency in the population databases [1000Genome, Exome Sequencing Project and ExAC]. In summary, the evidence meets our criteria for a Pathogenic classification. We have confirmed this finding in our laboratory using Sanger sequencing. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 368 of the HGD protein (p.Met368Val). This variant is present in population databases (rs120074173, gnomAD 0.04%). This missense change has been observed in individuals with alkaptonuria (PMID: 10340975, 19096913, 19862842). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3173). 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 expected to disrupt HGD protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HGD function (PMID: 10482952). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10340975, 19096913, 10465119, 31980526, 31589614, 35110678, 23430897, 25681086, 32158253, 16085442, 33621656, 19862842, 30737480, 33666743, 9529363, 10594001, 10482952, 10205262, 33072517) -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	-	- -

Intervertebral disk calcification Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Aug 19, 2022

ACMG categories: PS1,PS4,PM2,PM3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Pathogenic	3.5	M
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.010	D
Polyphen		0.91	P
Vest4		0.95
MVP		0.99
MPC		0.39
ClinPred		0.46	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.88
gMVP		0.87

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

LitVar

Other links and lift over

dbSNP: rs120074173; hg19: chr3-120352080;