rs146136265
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1PM2PM5PP5_Very_StrongBP4
The NM_001370658.1(BTD):c.1569C>A(p.Asp523Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000033 in 1,605,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. D523G) 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 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BTD | NM_001370658.1 | c.1569C>A | p.Asp523Glu | missense_variant | 4/4 | ENST00000643237.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BTD | ENST00000643237.3 | c.1569C>A | p.Asp523Glu | missense_variant | 4/4 | NM_001370658.1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000204 AC: 31AN: 152118Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000592 AC: 14AN: 236452Hom.: 0 AF XY: 0.0000463 AC XY: 6AN XY: 129660
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1452898Hom.: 0 Cov.: 31 AF XY: 0.0000207 AC XY: 15AN XY: 722982
GnomAD4 genome ? AF: 0.000204 AC: 31AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16AN XY: 74298
ClinVar
Submissions by phenotype
Biotinidase deficiency Pathogenic:6
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Mar 30, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 543 of the BTD protein (p.Asp543Glu). This variant is present in population databases (rs146136265, gnomAD 0.06%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 25174816, 25967232, 28498829). ClinVar contains an entry for this variant (Variation ID: 25103). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 22, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Mar 03, 2020 | ACMG classification criteria: PS4, PM2, PM3, PP2 - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 24, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 26, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as D543E; This variant is associated with the following publications: (PMID: 25967232, 26810761, 25174816, 22698809, 28498829, 35167647, 31801038) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 03, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at