chr3-120633233-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 7.46

Variant links:

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]

HGD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

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 rank	MANE	Protein	UniProt
HGD	NM_000187.4 link	c.1102A>G	p.Met368Val	missense_variant	Exon 13 of 14	ENST00000283871.10	NP_000178.2	Q93099
HGD	XM_005247412.3 link	c.877A>G	p.Met293Val	missense_variant	Exon 11 of 12		XP_005247469.1
HGD	XM_017006277.3 link	c.679A>G	p.Met227Val	missense_variant	Exon 13 of 14		XP_016861766.1	B3KW64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HGD	ENST00000283871.10 link	c.1102A>G	p.Met368Val	missense_variant	Exon 13 of 14	1	NM_000187.4	ENSP00000283871.5	Q93099
HGD	ENST00000470321.1 link	n.442A>G		non_coding_transcript_exon_variant	Exon 3 of 3	3
HGD	ENST00000492108.5 link	n.*84A>G		non_coding_transcript_exon_variant	Exon 5 of 6	2		ENSP00000419838.1	H7C5G7
HGD	ENST00000492108.5 link	n.*84A>G		3_prime_UTR_variant	Exon 5 of 6	2		ENSP00000419838.1	H7C5G7

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152134

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:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000706

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000167

AC:

AN:

251288

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135798

show subpopulations

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.:

Cov.:

AF XY:

0.000195

AC XY:

142

AN XY:

727240

show subpopulations

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:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74454

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:

0.000188

Gnomad4 NFE

AF:

0.000706

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000392

Hom.:

Bravo

AF:

0.000246

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alkaptonuria

Pathogenic:8Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
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, 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 [BeltrÃ¡n-Valero de BernabÃ© 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 [RodrÃguez 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, 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	Counsyl	Dec 18, 2015	- -
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 (BeltrÃ¡n-Valero de BernabÃ© et al. 1998; BeltrÃ¡n-Valero de BernabÃ© et al. 1999a; BeltrÃ¡n-Valero de BernabÃ© 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	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2025	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt HGD protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HGD function (PMID: 10482952). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:3

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	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Mar 04, 2025	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	-	- -

See cases

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

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.98

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.83

MetaSVM

Pathogenic

1.2

MutationAssessor

Pathogenic

3.5

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.010

Polyphen

0.91

Vest4

0.95

MVP

0.99

MPC

0.39

ClinPred

0.46

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

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