chr3-15644384-G-T
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001370658.1(BTD):c.468G>T(p.Lys156Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,614,156 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 Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000022 ( 0 hom. )
Consequence
BTD
NM_001370658.1 missense
NM_001370658.1 missense
Scores
2
6
4
Clinical Significance
Conservation
PhyloP100: 0.768
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, 0.948
PP5
Variant 3-15644384-G-T is Pathogenic according to our data. Variant chr3-15644384-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 25018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644384-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BTD | NM_001370658.1 | c.468G>T | p.Lys156Asn | missense_variant | 4/4 | ENST00000643237.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BTD | ENST00000643237.3 | c.468G>T | p.Lys156Asn | missense_variant | 4/4 | NM_001370658.1 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152148Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000955 AC: 24AN: 251394Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135850
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GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461890Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 727248
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GnomAD4 genome AF: 0.0000328 AC: 5AN: 152266Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74458
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Biotinidase deficiency Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 30, 2022 | Variant summary: BTD c.468G>T (p.Lys156Asn) 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 9.5e-05 in 251394 control chromosomes, predominantly at a frequency of 0.00069 within the Latino subpopulation in the gnomAD database. This frequency is not higher than predicted for a pathogenic variant in BTD causing Biotinidase Deficiency (9.5e-05 vs 0.0046). c.468G>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Biotinidase Deficiency (example: Cowan_2012). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all 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 | Baylor Genetics | Mar 30, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 22, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 176 of the BTD protein (p.Lys176Asn). This variant is present in population databases (rs397514367, gnomAD 0.08%). This missense change has been observed in individual(s) with profound biotinidase deficiency (<10% normal activity) (PMID: 10400129, 22698809). ClinVar contains an entry for this variant (Variation ID: 25018). 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, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jun 20, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 11, 2023 | The c.468G>T; p.Lys156Asn variant (rs397514367) is reported in the literature in the homozygous or compound heterozygous state in multiple Hispanic individuals affected with biotinidase deficiency (Cowan 2012, Norrgard 1999, Procter 2016). This variant is reported in ClinVar (Variation ID: 25018) and is found in the Latino population with an allele frequency of 0.074% (26/35434 alleles) in the Genome Aggregation Database. The lysine at codon 176 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.633). Based on available information, this variant is considered to be pathogenic. References: Cowan TM et al. Increased incidence of profound biotinidase deficiency among Hispanic newborns in California. Mol Genet Metab. 2012 Aug;106(4):485-7. PMID: 22698809 Norrgard K 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 46(1):20-7. PMID: 10400129 Procter M et al. Forty-eight novel mutations causing biotinidase deficiency. Mol Genet Metab. 2016 Mar;117(3):369-72. PMID: 26810761 - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 23, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 13, 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, 17382128, 26334177, 22698809, 10400129, 26810761) - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 09, 2020 | The c.528G>T (p.Lys176Asn) BTD pathogenic variant (also known as K176N) has been reported in multiple individuals with biotinidase deficiency (PMID: 26810761 (2016), 22698809 (2012), 1668630 (1991)). Individuals who are homozygous for the c.528G>T (p.Lys176Asn) BTD pathogenic variant have been described as having profound biotinidase deficiency with low biotinyl hydrolase activity, low biotinyl transferase activity, and low serum levels of cross reacting material to antibody prepared against purified human serum biotinidase (PMID: 10400129 (1999)). - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 06, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
Polyphen
1.0
.;.;D;.;.;.;.;.
Vest4
0.75, 0.80, 0.73
MutPred
0.87
.;.;Loss of ubiquitination at K176 (P = 0.0148);.;.;.;.;.;
MVP
0.93
MPC
0.45
ClinPred
D
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