rs146015592
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong
The NM_001370658.1(BTD):c.410G>A(p.Arg137His) variant causes a missense change. The variant allele was found at a frequency of 0.000208 in 1,613,628 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R137C) has been classified as Likely pathogenic.
Frequency
Genomes: 𝑓 0.00015 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00021 ( 1 hom. )
Consequence
BTD
NM_001370658.1 missense
NM_001370658.1 missense
Scores
1
13
5
Clinical Significance
Conservation
PhyloP100: 4.28
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.
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001370658.1
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-15644325-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 25012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP5
Variant 3-15644326-G-A is Pathogenic according to our data. Variant chr3-15644326-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 38290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644326-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BTD | NM_001370658.1 | c.410G>A | p.Arg137His | missense_variant | 4/4 | ENST00000643237.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BTD | ENST00000643237.3 | c.410G>A | p.Arg137His | missense_variant | 4/4 | NM_001370658.1 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 151918Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000108 AC: 27AN: 250768Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135574
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GnomAD4 exome AF: 0.000214 AC: 313AN: 1461710Hom.: 1 Cov.: 31 AF XY: 0.000202 AC XY: 147AN XY: 727148
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GnomAD4 genome AF: 0.000151 AC: 23AN: 151918Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8AN XY: 74174
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Biotinidase deficiency Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 157 of the BTD protein (p.Arg157His). This variant is present in population databases (rs146015592, gnomAD 0.02%). This missense change has been observed in individual(s) with biotinidase deficicency (PMID: 9396567, 11313766, 20224900, 22698809). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 38290). 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 25, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jan 05, 2022 | The c.410G>A;p.(Arg137His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 38290; PMID: 27329734; 26361991; 25754625; 23644139; 22698809; 20224900; 11313766) - PS4.The variant is located in a mutational hot spot and/or critical and well-established functional domain (CN_hydrolase domain) - PM1. The variant is present at low allele frequencies population databases (rs146015592– gnomAD 0.001514%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg137His) was detected in trans with a pathogenic variant (PMID: 27329734; 26361991; 25754625; 23644139; 22698809; 20224900; 11313766) - PM3_strong. Pathogenic missense variant in this residue have been reported (Clinvar ID: 25012) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 24, 2019 | NM_000060.2(BTD):c.470G>A(R157H) is classified as pathogenic in the context of biotinidase deficiency. Please note that R157H is seen in patients with both partial and profound biotinidase deficiency. Sources cited for classification include the following: PMID 23644139, 11313766, 16435182, 25754625, 9396567, 27329734 and 26361991. Classification of NM_000060.2(BTD):c.470G>A(R157H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 08, 2021 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 11668630, 25423671, 26361991, 27657684, 33123633, 32440248, 33189081, 9396567, 23644139, 25754625, 34426522) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 26, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 16, 2022 | In the published literature, this variant has reported as one of the most common pathogenic variants associated with biotinidase deficiency in Turkish population (PMIDs: 25754625 (2015), 29353266 (2018), and 33189081 (2021)). This variant has been identified in homozygous state or compound heterozygous state with other pathogenic BTD variants in multiple individuals with profound to partial biotinidase deficiency (PMIDs: 9396567 (1997), 10801053 (2000), 11313766 (2001), 16435182 (2005), 22698809 (2012), 25754625 (2015), 27329734, (2016), 29353266 (2018), and 33189081 (2021)). Therefore, this individual is at least a carrier of biotinidase deficiency. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
.;.;D;.;.;.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;.;.;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;.;M;.;.;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
.;D;.;.;.;D;D;D
REVEL
Uncertain
Sift
Benign
.;D;.;.;.;D;D;D
Sift4G
Uncertain
.;D;.;.;.;T;D;D
Polyphen
0.18
.;.;B;.;.;.;.;.
Vest4
0.58, 0.70, 0.62
MVP
0.94
MPC
0.12
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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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