rs369517993
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_000187.4(HGD):c.140C>T(p.Ser47Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,611,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S47S) has been classified as Likely benign.
Frequency
Consequence
NM_000187.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HGD | NM_000187.4 | c.140C>T | p.Ser47Leu | missense_variant | 3/14 | ENST00000283871.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HGD | ENST00000283871.10 | c.140C>T | p.Ser47Leu | missense_variant | 3/14 | 1 | NM_000187.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152104Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251280Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135814
GnomAD4 exome AF: 0.00000480 AC: 7AN: 1459626Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 4AN XY: 726214
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74412
ClinVar
Submissions by phenotype
Alkaptonuria Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 26, 2022 | The p.Ser47Leu variant in HGD has been reported in 5 individuals with alkaptonuria either as homozygous or compound heterozygous with a pathogenic variant (Zatkova 2001 PMID: 11017803, Ascher 2019 PMID: 30737480), and was absent in large population databases. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive alkaptonuria. ACMG/AMP criteria applied: PM3_Strong, PM2_Supporting, PP3. - |
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 described in AKU patients in PMID:23430897 and PMID:30737480. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00010). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at