rs138818907
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_001370658.1(BTD):โc.1429C>Tโ(p.Pro477Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000335 in 1,614,204 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 Likely pathogenic (โ โ ).
Frequency
Genomes: ๐ 0.00012 ( 0 hom., cov: 32)
Exomes ๐: 0.000025 ( 0 hom. )
Consequence
BTD
NM_001370658.1 missense
NM_001370658.1 missense
Scores
6
4
2
Clinical Significance
Conservation
PhyloP100: 4.77
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 16 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001370658.1
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.981
PP5
?
Variant 3-15645345-C-T is Pathogenic according to our data. Variant chr3-15645345-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 25094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15645345-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BTD | NM_001370658.1 | c.1429C>T | p.Pro477Ser | missense_variant | 4/4 | ENST00000643237.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BTD | ENST00000643237.3 | c.1429C>T | p.Pro477Ser | missense_variant | 4/4 | NM_001370658.1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000112 AC: 17AN: 152196Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251394Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135868
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GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461890Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17AN XY: 727244
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GnomAD4 genome ? AF: 0.000118 AC: 18AN: 152314Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74480
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Biotinidase deficiency Pathogenic:8
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Dec 21, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 02, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 497 of the BTD protein (p.Pro497Ser). This variant is present in population databases (rs138818907, gnomAD 0.04%). This missense change has been observed in individual(s) with with profound biotinidase deficiency and in combination with other variants in individuals with partial biotinidase deficiency (PMID: 10400129, 15776412, 19757147, 20224900, 25754625, 26361991, 26810761). ClinVar contains an entry for this variant (Variation ID: 25094). 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 | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense c.1429C>T (p.Pro477Ser) variant in BTD gene has been reported previously in both homozygous and compound heterozygous state in multiple individuals affected with profound biotinidase deficiency (Sarafoglou et al. 2009; Kasapkara et al.2015; Procter et al. 2016). The p.Pro477Ser variant is reported with an allele frequency of 0.002% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Pro477Ser in BTD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Pro at position 477 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. Additional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 14, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 10, 2022 | Variant summary: BTD c.1429C>T (p.Pro477Ser) results in a non-conservative amino acid change in the Vanin, C-terminal domain (IPR043957) of 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 3.9e-05 in 282800 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in BTD causing Biotinidase Deficiency (3.9e-05 vs 0.0046), allowing no conclusion about variant significance. c.1429C>T has been reported in the literature in multiple compound heterozygous (e.g. Norrgard_1999, Sarafoglou_2009, Kasapkara_2015) and homozygous (e.g. Sarafoglou_2009, Ercan_2021) individuals affected mostly with profound Biotinidase Deficiency. These data indicate that the variant is very likely to be associated with disease. Seven ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and six as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 27, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 15, 2022 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25087612, 15776412, 26589311, 19757147, 25423671, 25754625, 20224900, 24516753, 29353266, 25967232, 28498829, 26361991, 26810761, 10400129) - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 09, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 10, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Al Jalila Childrenโs Genomics Center, Al Jalila Childrens Speciality Hospital | Dec 17, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Benign
T
Polyphen
1.0
.;.;D;.;.;.;.
Vest4
0.92, 0.94, 0.92
MVP
1.0
MPC
0.42
ClinPred
D
GERP RS
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