rs80338686
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_001370658.1(BTD):c.1552C>A(p.Arg518Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,456,588 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R518L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001370658.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BTD | NM_001370658.1 | c.1552C>A | p.Arg518Ser | missense_variant | 4/4 | ENST00000643237.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BTD | ENST00000643237.3 | c.1552C>A | p.Arg518Ser | missense_variant | 4/4 | NM_001370658.1 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000332 AC: 8AN: 240906Hom.: 0 AF XY: 0.0000532 AC XY: 7AN XY: 131570
GnomAD4 exome AF: 0.0000110 AC: 16AN: 1456588Hom.: 0 Cov.: 32 AF XY: 0.0000152 AC XY: 11AN XY: 724720
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Biotinidase deficiency Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 24, 2023 | This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 538 of the BTD protein (p.Arg538Ser). This variant is present in population databases (rs80338686, gnomAD 0.03%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 22698809; Invitae). ClinVar contains an entry for this variant (Variation ID: 203642). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BTD protein function with a positive predictive value of 95%. This variant disrupts the p.Arg538 amino acid residue in BTD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9099842, 26810761, 27207447). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 17, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 08, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Arcensus | Feb 01, 2013 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 16, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at