rs28941783

Positions:

• chr3-120647041-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000187.4(HGD):​c.481G>A​(p.Gly161Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000917 in 1,613,870 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 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: HGD NM_000187.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 7.18

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 16 ACMG points.

• PM1: In a strand (size 17) in uniprot entity HGD_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_000187.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 3-120647041-C-T is Pathogenic according to our data. Variant chr3-120647041-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-120647041-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HGD	NM_000187.4	c.481G>A	p.Gly161Arg	missense_variant	8/14	ENST00000283871.10	NP_000178.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HGD	ENST00000283871.10	c.481G>A	p.Gly161Arg	missense_variant	8/14	1	NM_000187.4	ENSP00000283871.5
HGD	ENST00000476082.2	c.358G>A	p.Gly120Arg	missense_variant	7/7	5		ENSP00000419560.2
HGD	ENST00000475447.2	c.10G>A	p.Gly4Arg	missense_variant	1/5	3		ENSP00000417977.2
HGD	ENST00000492108.5	n.112G>A		non_coding_transcript_exon_variant	3/6	2		ENSP00000419838.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152170 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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000876 AC: 22 AN: 251104 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135696

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000848 AC: 124 AN: 1461700 Hom.: 0 Cov.: 31 AF XY: 0.000106 AC XY: 77 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 NFE exome AF: 0.000105

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74340

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: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000279 Hom.: 0

Bravo AF: 0.000144

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alkaptonuria Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 161 of the HGD protein (p.Gly161Arg). This variant is present in population databases (rs28941783, gnomAD 0.03%). This missense change has been observed in individuals with alkaptonuria (PMID: 9154114, 12051967, 19862842, 20462779). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3168). 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 HGD protein function with a negative 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	Illumina Laboratory Services, Illumina	Apr 05, 2019	Across a selection of the available literature, the HGD c.481G>A (p.Gly161Arg) missense variant has been identified in 55 individuals with alkaptonuria, including in a homozygous state in 27 individuals and in a compound heterozygous state in 38 individuals, and is also found in a heterozygous state in 25 unaffected individuals (Gehrig et al. 1997; Vilboux et al. 2009; Zatkova et al. 2012; Usher et al. 2015; Nemethova et al. 2015; Cieszynski et al. 2016). The p.Gly161Arg variant was also shown to segregate with disease in a three-generation family with one affected homozygote (Gehrig et al. 1997). The variant was absent from 384 control chromosomes but is reported at a frequency of 0.000269 in the European (non-Finnish) population of the Genome Aggregation Database. The Gly161 residue is conserved. Variant enzyme activity assays performed in E. coli demonstarted that the p.Gly161Arg variant resulted in one percent activity in comparison to wild type (Rodriguez et al. 2000). Based on the collective evidence, the p.Gly161Arg 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, no assertion criteria provided	literature only	OMIM	Jul 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 10, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 09, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PS3, PM2, PP2, PP3, PP4, PP5 -
not provided, no classification provided	literature only	GeneReviews	-	1 of 4 founder variants in the Slovak population -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 20, 2020	- -
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:9154114. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00050). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2023	Published functional studies demonstrate a damaging effect as biochemical analysis show that this variant leads to a protein with no enzymatic activity (Ascher et al., 2019; Mller et al., 1999); 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: 20462779, 34426522, 34008892, 31589614, 33072517, 19862842, 25804398, 37395296, 11001939, 10970188, 12051967, 33621656, 25681086, 34504318, 27026014, 9154114, 10482952, 30737480) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.9	H;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-8.0	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		1.0
MutPred		0.97		Gain of methylation at K160 (P = 0.05);.;
MVP		0.99
MPC		0.53
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.94
gMVP		0.96

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: rs28941783; hg19: chr3-120365888;