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rs397515516

chr3-120633223-TG-Tchr3-120633223-TG-TGG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
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 20 pathogenic variants in the truncated region.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
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 UniProt
HGDNM_000187.4 linkuse as main transcriptc.1111del p.His371MetfsTer34 frameshift_variant 13/14 ENST00000283871.10
HGDXM_005247412.3 linkuse as main transcriptc.886del p.His296MetfsTer34 frameshift_variant 11/12
HGDXM_017006277.3 linkuse as main transcriptc.688del p.His230MetfsTer34 frameshift_variant 13/14

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HGDENST00000283871.10 linkuse as main transcriptc.1111del p.His371MetfsTer34 frameshift_variant 13/141 NM_000187.4 P1
HGDENST00000470321.1 linkuse as main transcriptn.451del non_coding_transcript_exon_variant 3/33
HGDENST00000492108.5 linkuse as main transcriptc.*93del 3_prime_UTR_variant, NMD_transcript_variant 5/62

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461882
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
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
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Alkaptonuria Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeMay 13, 2021This 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.

Other links and lift over

hg19: chr3-120352070; API