rs397515517

chr3-120674901-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000187.4(HGD):c.175del(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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 6.97

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 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/exons	MANE	UniProt
HGD	NM_000187.4	c.175del	p.Ser59AlafsTer52	frameshift_variant, splice_region_variant	3/14	ENST00000283871.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HGD	ENST00000283871.10	c.175del	p.Ser59AlafsTer52	frameshift_variant, splice_region_variant	3/14	1	NM_000187.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152112 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: 0.000621

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: 30 AN: 251276 Hom.: 0 AF XY: 0.000191 AC XY: 26 AN XY: 135810

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.: 0 Cov.: 27 AF XY: 0.000111 AC XY: 80 AN XY: 721478

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: 4 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74442

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.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alkaptonuria Pathogenic:7 Other: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:10594001. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00013). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 22, 2023	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. -
not provided, no classification provided	literature only	GeneReviews	-	Frequent frameshift variant -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 09, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 26, 2022	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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

May 03, 2020

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs397515517; hg19: chr3-120393748;