rs397514364
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The NM_001370658.1(BTD):c.425C>T(p.Ala142Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,826 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A142P) has been classified as Pathogenic.
Frequency
Consequence
NM_001370658.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BTD | NM_001370658.1 | c.425C>T | p.Ala142Val | missense_variant | 4/4 | ENST00000643237.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BTD | ENST00000643237.3 | c.425C>T | p.Ala142Val | missense_variant | 4/4 | NM_001370658.1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151990Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251188Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135782
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461836Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727216
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151990Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74204
ClinVar
Submissions by phenotype
Biotinidase deficiency Pathogenic:3Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 26, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 06, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 11, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 162 of the BTD protein (p.Ala162Val). This variant is present in population databases (rs397514364, gnomAD 0.0009%). This missense change has been observed in individual(s) with BTD-related conditions (PMID: 25144890, 27657684). ClinVar contains an entry for this variant (Variation ID: 25014). 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. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 09, 2021 | The BTD c.485C>T; p.Ala162Val variant (rs397514364) is reported in the literature in multiple individuals affected with partial to profound biotinidase deficiency usually found with a second pathogenic variant (Norrgard 1999, Wolf 2017). This variant is reported in ClinVar (Variation ID: 25014) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 162 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.928). Based on available information, this variant is considered to be pathogenic. References: Norrgard KJ et al. Mutations causing profound biotinidase deficiency in children ascertained by newborn screening in the United States occur at different frequencies than in symptomatic children. Pediatr Res. 1999 Jul;46(1):20-7. PMID: 10400129. Wolf B et al. Successful outcomes of older adolescents and adults with profound biotinidase deficiency identified by newborn screening. Genet Med. 2017 Apr;19(4):396-402. PMID: 27657684. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at