3-120628449-G-T

Variant names:

• chr3-120628449-G-T
• NM_000187.4:c.1269C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_000187.4(HGD):​c.1269C>A​(p.Tyr423*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HGD NM_000187.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.63

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0516 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-120628449-G-T is Pathogenic according to our data. Variant chr3-120628449-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1458490.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGD	NM_000187.4	c.1269C>A	p.Tyr423*	stop_gained	Exon 14 of 14	ENST00000283871.10	NP_000178.2
HGD	XM_005247412.3	c.1044C>A	p.Tyr348*	stop_gained	Exon 12 of 12		XP_005247469.1
HGD	XM_017006277.3	c.846C>A	p.Tyr282*	stop_gained	Exon 14 of 14		XP_016861766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGD	ENST00000283871.10	c.1269C>A	p.Tyr423*	stop_gained	Exon 14 of 14	1	NM_000187.4	ENSP00000283871.5
HGD	ENST00000492108.5	n.*251C>A		non_coding_transcript_exon_variant	Exon 6 of 6	2		ENSP00000419838.1
HGD	ENST00000492108.5	n.*251C>A		3_prime_UTR_variant	Exon 6 of 6	2		ENSP00000419838.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Alkaptonuria Pathogenic:1

Jul 08, 2021

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.Tyr423*) in the HGD gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 23 amino acid(s) of the HGD protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with HGD-related conditions. This variant disrupts a region of the HGD protein in which other variant(s) (p.Lys431Hisfs*11) have been determined to be pathogenic (PMID: 23430897, 25681086; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.92
GERP RS		2.2

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-120347296;