rs28941783

chr3-120647041-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G161E) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000085 ( 0 hom. )

Consequence

HGD
NM_000187.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 7.18

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 18 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_000187.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-120647040-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2101494.Status of the report is criteria_provided_single_submitter, 1 stars.

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	UniProt
HGD	NM_000187.4 linkuse as main transcript	c.481G>A	p.Gly161Arg	missense_variant	8/14	ENST00000283871.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HGD	ENST00000283871.10 linkuse as main transcript	c.481G>A	p.Gly161Arg	missense_variant	8/14	1	NM_000187.4	P1
HGD	ENST00000476082.2 linkuse as main transcript	c.358G>A	p.Gly120Arg	missense_variant	7/7	5
HGD	ENST00000475447.2 linkuse as main transcript	c.13G>A	p.Gly5Arg	missense_variant	1/5	3
HGD	ENST00000492108.5 linkuse as main transcript	c.112G>A	p.Gly38Arg	missense_variant, NMD_transcript_variant	3/6	2

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152170

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000876

AC:

AN:

251104

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135696

show subpopulations

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.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

727182

show subpopulations

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:

AN:

152170

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74340

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:

0.00

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000279

Hom.:

Bravo

AF:

0.000144

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alkaptonuria

Pathogenic:8Other:1

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, 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, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PS3, PM2, PP2, PP3, PP4, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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	Fulgent Genetics, Fulgent Genetics	Aug 04, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 09, 2016	- -
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. -

not provided

Pathogenic:1

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

BayesDel_noAF

Pathogenic

0.56

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

3.9

H;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.74

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

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

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