chr3-15645469-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_001370658.1(BTD):c.1553G>A(p.Arg518His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000056 in 1,608,274 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.1553G>A | p.Arg518His | missense_variant | 4/4 | ENST00000643237.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BTD | ENST00000643237.3 | c.1553G>A | p.Arg518His | missense_variant | 4/4 | NM_001370658.1 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152160Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000416 AC: 1AN: 240284Hom.: 0 AF XY: 0.00000762 AC XY: 1AN XY: 131310
GnomAD4 exome AF: 0.00000481 AC: 7AN: 1456114Hom.: 0 Cov.: 32 AF XY: 0.00000552 AC XY: 4AN XY: 724486
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74334
ClinVar
Submissions by phenotype
Biotinidase deficiency Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 30, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 17, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The observed missense c.1553G>A (p.Arg518His) variant in gene has been reported in compound heterozygous state in individuals affected with Biotinidase deficiency (Procter M et al. 2016). Experimental studies have shown that this missense change affects BTD function (Liu Z et al. 2018). The variant p.Arg518His has allele frequency 0.0004% in gnomAD. This variant has been submitted to the ClinVar database as likely Pathogenic / Pathogenic. The amino acid change p.Arg518His in BTD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 518 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 24, 2023 | For these reasons, this variant has been classified as Pathogenic. 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, 22698809, 27207447, 27657684). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects BTD function (PMID: 29359854). 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. ClinVar contains an entry for this variant (Variation ID: 25099). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 19757147, 26810761, 29359854; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs397514429, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 538 of the BTD protein (p.Arg538His). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 12, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R538H); This variant is associated with the following publications: (PMID: 19757147, 29359854, 26810761, 22698809, 9099842, 27657684, 27207447, 37564434) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at