rs200337373
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BP6
The NM_001370658.1(BTD):c.604G>A(p.Asp202Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000188 in 1,613,976 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).
Frequency
Consequence
NM_001370658.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BTD | NM_001370658.1 | c.604G>A | p.Asp202Asn | missense_variant | Exon 4 of 4 | ENST00000643237.3 | NP_001357587.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000132 AC: 20AN: 152082Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000123 AC: 31AN: 251478Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135912
GnomAD4 exome AF: 0.000194 AC: 283AN: 1461894Hom.: 0 Cov.: 31 AF XY: 0.000193 AC XY: 140AN XY: 727248
GnomAD4 genome AF: 0.000132 AC: 20AN: 152082Hom.: 0 Cov.: 31 AF XY: 0.000162 AC XY: 12AN XY: 74278
ClinVar
Submissions by phenotype
Biotinidase deficiency Uncertain:3
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 222 of the BTD protein (p.Asp222Asn). This variant is present in population databases (rs200337373, gnomAD 0.02%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 25174816, 28498829). ClinVar contains an entry for this variant (Variation ID: 381650). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect BTD function (PMID: 31337602). This variant disrupts the p.Asp222 amino acid residue in BTD. Other variant(s) that disrupt this residue have been observed in individuals with BTD-related conditions (PMID: 22698809, 26810761), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
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Inborn genetic diseases Uncertain:1
The c.664G>A (p.D222N) alteration is located in exon 4 (coding exon 4) of the BTD gene. This alteration results from a G to A substitution at nucleotide position 664, causing the aspartic acid (D) at amino acid position 222 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not specified Benign:1
Variant summary: BTD c.604G>A (p.Asp202Asn) results in a conservative amino acid change located in the Nitrilase/Amidase homologous domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 273024 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BTD causing Biotinidase Deficiency (0.00011 vs 0.0046), allowing no conclusion about variant significance. c.604G>A has been reported in the literature in individuals affected with Biotinidase Deficiency (Borsatto_2014) or Ovarian Cancer (Permuth_2016). These reports do not provide unequivocal conclusions about association of the variant with Biotinidase Deficiency. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Borsatto_2019). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
not provided Benign:1
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31337602, 25174816, 27378695) -
Intellectual disability Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at