3-120628429-AG-A

Variant names:

• chr3-120628429-AG-A
• NM_000187.4:c.1288delC

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.1288delC​(p.Leu430SerfsTer24) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HGD NM_000187.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.25

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 0.0374 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 3-120628429-AG-A is Pathogenic according to our data. Variant chr3-120628429-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 1071828.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.1288delC	p.Leu430SerfsTer24	frameshift_variant	Exon 14 of 14	ENST00000283871.10	NP_000178.2
HGD	XM_005247412.3	c.1063delC	p.Leu355SerfsTer24	frameshift_variant	Exon 12 of 12		XP_005247469.1
HGD	XM_017006277.3	c.865delC	p.Leu289SerfsTer24	frameshift_variant	Exon 14 of 14		XP_016861766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGD	ENST00000283871.10	c.1288delC	p.Leu430SerfsTer24	frameshift_variant	Exon 14 of 14	1	NM_000187.4	ENSP00000283871.5
HGD	ENST00000492108.5	n.*270delC		non_coding_transcript_exon_variant	Exon 6 of 6	2		ENSP00000419838.1
HGD	ENST00000492108.5	n.*270delC		3_prime_UTR_variant	Exon 6 of 6	2		ENSP00000419838.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461790 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727212

Gnomad4 AFR exome AF: 0.0000299

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

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Alkaptonuria Pathogenic:1

Aug 06, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the HGD protein. Other variant(s) that disrupt this region (p.Lys431Hisfs*11) have been determined to be pathogenic (PMID: 23430897, 25681086, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has not been reported in the literature in individuals with HGD-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change results in a frameshift in the HGD gene (p.Leu430Serfs*24). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acids of the HGD protein and extend the protein by an additional 7 amino acids. -

Computational scores

Source: dbNSFP v4.3

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: chr3-120347276;