rs397514369
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001370658.1(BTD):c.497G>A(p.Cys166Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,890 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.000010 ( 1 hom. )
Consequence
BTD
NM_001370658.1 missense
NM_001370658.1 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 9.98
Genes affected
BTD (HGNC:1122): (biotinidase) The protein encoded by this gene functions to recycle protein-bound biotin by cleaving biocytin (biotin-epsilon-lysine), a normal product of carboxylase degradation, resulting in regeneration of free biotin. The encoded protein has also been shown to have biotinyl transferase activity. Mutations in this gene are associated with biotinidase deficiency. Multiple transcript variants encoding different isoforms have been described. [provided by RefSeq, Aug 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant 3-15644413-G-A is Pathogenic according to our data. Variant chr3-15644413-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 25020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644413-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BTD | NM_001370658.1 | c.497G>A | p.Cys166Tyr | missense_variant | 4/4 | ENST00000643237.3 | NP_001357587.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BTD | ENST00000643237.3 | c.497G>A | p.Cys166Tyr | missense_variant | 4/4 | NM_001370658.1 | ENSP00000495254 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
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31
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251430Hom.: 1 AF XY: 0.0000294 AC XY: 4AN XY: 135874
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461890Hom.: 1 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727244
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GnomAD4 genome Cov.: 31
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Biotinidase deficiency Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 03, 2024 | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 186 of the BTD protein (p.Cys186Tyr). This variant is present in population databases (rs397514369, gnomAD 0.02%). This missense change has been observed in individual(s) with profound or partial biotinidase deficiency, and suspected BTD deficiency (PMID: 10801053, 22011816, 23644139, 25754625). ClinVar contains an entry for this variant (Variation ID: 25020). 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. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jul 11, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 03, 2022 | The p.Cys186Tyr variant in BTD has been reported in at least 4 compound heterozygous individuals with partial Biotinidase deficiency and reduced Biotinidase activity in their serum (Pomponio 2000 PubMed: 10801053; Ben-Rebeh 2012 PMID: 22106832; Thodi 2013 PMID: 23644139; Al Hosani 2014 PMID: 24932929) and in 15 newborns with Biotinidase deficiency (Karaca 2015 PMID: 25754625; Seker Yilmaz 2018 PMID: 29353266). It was also observed in ClinVar (Variation ID 25020) but absent in gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant disrupts a functional cysteine that is likely important for protein function (Karaca 2015 PMID: 25754625). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive partial Biotinidase deficiency. ACMG/AMP Criteria applied: PM3_VeryStrong, PM1_Supporting, PM2_Supporting, PP3, PP4. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 20, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 06, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 23, 2023 | Variant summary: BTD c.497G>A (p.Cys166Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251430 control chromosomes in the gnomAD database, including 1 homozygote. c.497G>A has been reported in the literature in multiple individuals affected with Biotinidase Deficiency, including a homozygous individual with profound biotinidase deficiency and compound heterozygous cases with other (likely) pathogenic variants (Ben-Rebeh_2012, Ercan_2020, Kasapkara_2015, Pomponio_2000, Thodi_2013). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 10801053, 33189081, 22011816, 23644139, 22106832, 25423671). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 11, 2012 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;.;D;.;.;.;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D;.;.;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;M;.;.;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;D;.;.;.;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
.;D;.;.;.;D;D;D
Sift4G
Pathogenic
.;D;.;.;.;D;D;D
Polyphen
1.0
.;.;D;.;.;.;.;.
Vest4
0.95, 0.97, 0.95
MutPred
0.91
.;.;Loss of methylation at K188 (P = 0.0714);.;.;.;.;.;
MVP
1.0
MPC
0.54
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at