Genetic Variant HGD:p.Ser59AlafsTer52 (chr3-120674901-CT-C) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000187.4(HGD):c.175delA(p.Ser59AlafsTer52) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.0000781 in 1,600,586 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000084 ( 0 hom. )

Consequence

HGD
NM_000187.4 frameshift, splice_region

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 6.97

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.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-120674901-CT-C is Pathogenic according to our data. Variant chr3-120674901-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 3171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-120674901-CT-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.175delA	p.Ser59AlafsTer52	frameshift_variant, splice_region_variant	Exon 3 of 14	ENST00000283871.10	NP_000178.2	Q93099

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGD	ENST00000283871.10 link	c.175delA	p.Ser59AlafsTer52	frameshift_variant, splice_region_variant	Exon 3 of 14	1	NM_000187.4	ENSP00000283871.5		Q93099

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152112

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:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000119

AC:

AN:

251276

Hom.:

AF XY:

0.000191

AC XY:

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000784

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000835

AC:

121

AN:

1448356

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

721478

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.000674

Gnomad4 FIN exome

AF:

0.000281

Gnomad4 NFE exome

AF:

0.0000373

Gnomad4 OTH exome

AF:

0.000100

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74442

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:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000790

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alkaptonuria

Pathogenic:11Other:1

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The variant was originally described in AKU patient in PMID:10594001. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00013). -

Jan 16, 2022

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser59Alafs*52) in the HGD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HGD are known to be pathogenic (PMID: 12501223, 19862842). This variant is present in population databases (rs587776556, gnomAD 0.08%). This premature translational stop signal has been observed in individual(s) with alkaptonuria (PMID: 10594001, 12872836, 18945288, 19862842, 25681086). It has also been observed to segregate with disease in related individuals. This variant is also known as p.R58fs. ClinVar contains an entry for this variant (Variation ID: 3171). For these reasons, this variant has been classified as Pathogenic. -

Apr 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Frequent frameshift variant -

Aug 26, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser59AlafsX52 variant in HGD has been reported in at least 7 individuals with alkaptonuria and segregated with disease in 5 affected individuals from 4 families (Beltran-Valero 1999 PMID: 10594001, Uyguner 2003 PMID: 12872836, Abdulrazzaq 2009 PMID: 18945288, Usher 2015 PMID:25681086, Akbaba 2020 PMID: 31927521). It has also been identified in 0.06% (3/4828) of South Asian and 0.001% (1/68026) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 3171). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 59 and leads to a premature termination codon 52 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the HGD gene is an established disease mechanism in autosomal recessive alkaptonuria. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive alkaptonuria. ACMG/AMP Criteria applied: PVS1, PP1_Strong, PM3_Strong. -

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1,PM3,PP1,PM2 -

Mar 09, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frameshift variant c.175del p.Ser59AlafsTer52 in the HGD gene has been reported previously in homozygous and compound heterozygous states in multiple individuals affected with Alkaptonuria Kisa et al., 2021; Usher et al., 2015. This c.175delA has been reported as the most common variant among Alkaptonuria patients. This variant is reported with the allele frequency 0.01% in the gnomAD Exomes and novel not in any individuals in 1000 Genomes. It is submitted to ClinVar as Pathogenic Multiple submissions. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

Mar 01, 2025

Department of Medical Genetics and Pathology, Ardabil University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Pathogenic:2

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HGD: PVS1, PM2, PM3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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