rs397515518
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_000187.4(HGD):c.342+1G>T variant causes a splice donor change. The variant allele was found at a frequency of 0.0000335 in 1,610,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000036 ( 0 hom. )
Consequence
HGD
NM_000187.4 splice_donor
NM_000187.4 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.05
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 16 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.044095665 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.9, offset of -6, new splice context is: tttGTgagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 3-120652591-C-A is Pathogenic according to our data. Variant chr3-120652591-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-120652591-C-A is described in Lovd as [Pathogenic]. Variant chr3-120652591-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HGD | NM_000187.4 | c.342+1G>T | splice_donor_variant | ENST00000283871.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HGD | ENST00000283871.10 | c.342+1G>T | splice_donor_variant | 1 | NM_000187.4 | P1 | |||
HGD | ENST00000476082.2 | c.219+1G>T | splice_donor_variant | 5 | |||||
HGD | ENST00000485313.5 | n.450+1G>T | splice_donor_variant, non_coding_transcript_variant | 5 | |||||
HGD | ENST00000488183.5 | downstream_gene_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152130Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250876Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135578
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GnomAD4 exome AF: 0.0000357 AC: 52AN: 1458226Hom.: 0 Cov.: 30 AF XY: 0.0000331 AC XY: 24AN XY: 725646
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Alkaptonuria Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 25, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 25, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 189127). This variant is also known as c.509+1G>T. Disruption of this splice site has been observed in individuals with alkaptonuria (PMID: 9529363, 10482952, 25681086). This variant is present in population databases (rs397515518, gnomAD 0.003%). This sequence change affects a donor splice site in intron 5 of the HGD gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HGD are known to be pathogenic (PMID: 12501223, 19862842). - |
Pathogenic, no assertion criteria provided | research | Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences | - | The variant was originally described in AKU patient in PMID:9529363. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00024). - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jan 15, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -48
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at