HGD p.Trp60*

Variant names:

• chr3-120670529-C-T
• NM_000187.4:c.180G>A
• HGD p.Trp60*

Your query was ambiguous. Multiple possible variants found:

• chr3-120670529-C-T
• chr3-120670530-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000187.4(HGD):​c.180G>A​(p.Trp60*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000142 in 1,410,468 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 (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HGD NM_000187.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.87
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• alkaptonuria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 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 3-120670529-C-T is Pathogenic according to our data. Variant chr3-120670529-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2584707.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000187.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HGD	NM_000187.4	MANE Select	c.180G>A	p.Trp60*	stop_gained	Exon 4 of 14	NP_000178.2	Q93099

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HGD	ENST00000283871.10	TSL:1 MANE Select	c.180G>A	p.Trp60*	stop_gained	Exon 4 of 14	ENSP00000283871.5	Q93099
	HGD	ENST00000898838.1		c.180G>A	p.Trp60*	stop_gained	Exon 4 of 15	ENSP00000568897.1
	HGD	ENST00000898833.1		c.180G>A	p.Trp60*	stop_gained	Exon 4 of 14	ENSP00000568892.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1410468 Hom.: 0 Cov.: 26 AF XY: 0.00000142 AC XY: 1 AN XY: 704882

African (AFR) AF: 0.00 AC: 0 AN: 32384

American (AMR) AF: 0.00 AC: 0 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25830

East Asian (EAS) AF: 0.00 AC: 0 AN: 39460

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1065118

Other (OTH) AF: 0.00 AC: 0 AN: 58714

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Alkaptonuria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		6.9
Mutation Taster		=1/199	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr3-120389376;