Variant rs397515516 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_000187.4(HGD):c.1111del(p.His371MetfsTer34) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.31

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-120633223-TG-T is Pathogenic according to our data. Variant chr3-120633223-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 1454693.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-120633223-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HGD	NM_000187.4 linkuse as main transcript	c.1111del	p.His371MetfsTer34	frameshift_variant	13/14	ENST00000283871.10	NP_000178.2
HGD	XM_005247412.3 linkuse as main transcript	c.886del	p.His296MetfsTer34	frameshift_variant	11/12		XP_005247469.1
HGD	XM_017006277.3 linkuse as main transcript	c.688del	p.His230MetfsTer34	frameshift_variant	13/14		XP_016861766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
HGD	ENST00000283871.10 linkuse as main transcript	c.1111del	p.His371MetfsTer34	frameshift_variant	13/14	1	NM_000187.4	ENSP00000283871	P1
HGD	ENST00000470321.1 linkuse as main transcript	n.451del		non_coding_transcript_exon_variant	3/3	3
HGD	ENST00000492108.5 linkuse as main transcript	c.*93del		3_prime_UTR_variant, NMD_transcript_variant	5/6	2		ENSP00000419838

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Alkaptonuria

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 13, 2021

This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.His371Metfs*34) in the HGD gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 75 amino acid(s) of the HGD protein. This variant has not been reported in the literature in individuals with HGD-related conditions. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over