rs786204662

Positions:

• chr3-120644440-GCC-G
• chr3-120644440-GCC-GC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000187.4(HGD):​c.651_652delGG​(p.Ala218fs) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: HGD NM_000187.4 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.38

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 12 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 3-120644440-GCC-G is Pathogenic according to our data. Variant chr3-120644440-GCC-G is described in ClinVar as [Pathogenic]. Clinvar id is 643931.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HGD	NM_000187.4	c.651_652delGG	p.Ala218fs	frameshift_variant, splice_region_variant	10/14	ENST00000283871.10	NP_000178.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HGD	ENST00000283871.10	c.651_652delGG	p.Ala218fs	frameshift_variant, splice_region_variant	10/14	1	NM_000187.4	ENSP00000283871.5
HGD	ENST00000494453.1	c.69_70delGG	p.Ala24fs	frameshift_variant, splice_region_variant	2/5	3		ENSP00000419163.1
HGD	ENST00000475447.2	c.200+156_200+157delGG		intron_variant		3		ENSP00000417977.2
HGD	ENST00000492108.5	n.180+2531_180+2532delGG		intron_variant		2		ENSP00000419838.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Alkaptonuria Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 31, 2018

This sequence change creates a premature translational stop signal (p.Ala218Glnfs*8) in the HGD gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with HGD-related disease. Loss-of-function variants in HGD are known to be pathogenic (PMID: 12501223, 19862842). For these reasons, this variant has been classified as Pathogenic. -

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

LitVar

Other links and lift over

dbSNP: rs786204662; hg19: chr3-120363287;