rs760206323
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000187.4(HGD):c.1188+1G>T variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,738 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
Consequence
NM_000187.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HGD | NM_000187.4 | c.1188+1G>T | splice_donor_variant | ENST00000283871.10 | |||
HGD | XM_005247412.3 | c.963+1G>T | splice_donor_variant | ||||
HGD | XM_017006277.3 | c.765+1G>T | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HGD | ENST00000283871.10 | c.1188+1G>T | splice_donor_variant | 1 | NM_000187.4 | P1 | |||
HGD | ENST00000492108.5 | c.*170+1G>T | splice_donor_variant, NMD_transcript_variant | 2 | |||||
HGD | ENST00000470321.1 | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250658Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135474
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461738Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727182
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Alkaptonuria Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 16, 2020 | 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with alkaptonuria (PMID: 11001939). ClinVar contains an entry for this variant (Variation ID: 370979). This variant is present in population databases (rs760206323, ExAC 0.005%). This sequence change affects a donor splice site in the last intron (intron 13) of the HGD gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. - |
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:11001939. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00101). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 26, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at