rs1057516467

Positions:

• chr3-120670530-C-T

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.179G>A​(p.Trp60Ter) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HGD NM_000187.4 stop_gained, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.87

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 3-120670530-C-T is Pathogenic according to our data. Variant chr3-120670530-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-120670530-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.179G>A	p.Trp60Ter	stop_gained, splice_region_variant	4/14	ENST00000283871.10	NP_000178.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HGD	ENST00000283871.10	c.179G>A	p.Trp60Ter	stop_gained, splice_region_variant	4/14	1	NM_000187.4	ENSP00000283871	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1401456 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 700790

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alkaptonuria Pathogenic:3

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:23430897. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00017). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 15, 2022	This sequence change creates a premature translational stop signal (p.Trp60*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with alkaptonuria (PMID: 23430897). ClinVar contains an entry for this variant (Variation ID: 370411). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 02, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A
Vest4		0.93
GERP RS		6.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs1057516467; hg19: chr3-120389377;