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rs13073139

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_001370658.1(BTD):c.451G>A(p.Ala151Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000527 in 1,613,968 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

Genomes: 𝑓 0.00035 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00055 ( 0 hom. )

Consequence

BTD
NM_001370658.1 missense

Scores

8
2
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:18U:1O:2

Conservation

PhyloP100: 10.0
Variant links:
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 Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.793
PP5
Variant 3-15644367-G-A is Pathogenic according to our data. Variant chr3-15644367-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38298.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=16, Uncertain_significance=1, not_provided=2}. Variant chr3-15644367-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BTDNM_001370658.1 linkuse as main transcriptc.451G>A p.Ala151Thr missense_variant 4/4 ENST00000643237.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BTDENST00000643237.3 linkuse as main transcriptc.451G>A p.Ala151Thr missense_variant 4/4 NM_001370658.1 P1P43251-4

Frequencies

GnomAD3 genomes
AF:
0.000348
AC:
53
AN:
152084
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000603
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000330
AC:
83
AN:
251332
Hom.:
0
AF XY:
0.000346
AC XY:
47
AN XY:
135832
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000651
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000546
AC:
798
AN:
1461884
Hom.:
0
Cov.:
31
AF XY:
0.000535
AC XY:
389
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000684
Gnomad4 OTH exome
AF:
0.000397
GnomAD4 genome
AF:
0.000348
AC:
53
AN:
152084
Hom.:
0
Cov.:
31
AF XY:
0.000242
AC XY:
18
AN XY:
74282
show subpopulations
Gnomad4 AFR
AF:
0.000169
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000603
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000616
Hom.:
0
Bravo
AF:
0.000404
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000581
AC:
5
ExAC
AF:
0.000387
AC:
47
EpiCase
AF:
0.000491
EpiControl
AF:
0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:18Uncertain:1Other:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Biotinidase deficiency Pathogenic:10Uncertain:1Other:2
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 30, 2018Across a selection of the available literature, the BTD c.511G>A (p.Ala171Thr) variant has been found as part of a complex allele [p.Ala171Thr;p.Asp444His] in a majority of cases including 25 individuals, a majority of whom were newborns, with the variant in a compound heterozygous state, 20 with profound biotinidase deficiency, four with partial biotinidase deficiency, and one individual who did not have information on biotinidase activity (Norrgard et al. 1998; Norrgard et al. 1999; Borsatto et al. 2014; Borsatto et al. 2017). The second variant identified in the compound heterozygous individuals was most often a missense variant. The complex allele has also been reported in a homozygous state in three individuals with profound biotinidase deficiency including a father-daughter pair from a consanguineous family where one parent and two grandparents were all heterozygous carriers of the variant and were unaffected (Wolf et al. 1997). A study by Lindau-Shepart et al. (2012) also identified the p.Ala171Thr variant in at least ten patients without the p.Asp444His variant, including five with a different second variant, but in whom zygosity was not specified. In addition, since a limited number of variants were evaluated in this study, the authors suggest that a less common variant may also be present with the p.Ala171Thr variant in the five individuals with a single variant detected. The p.Ala171Thr variant was absent from 376 normal blood spots and is reported at a frequency of 0.00066 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence, the p.Ala171Thr variant is classified as pathogenic for biotinidase deficiency. -
Pathogenic, criteria provided, single submitterclinical testingDASAFeb 14, 2022The c.451G>A;p.(Ala151Thr) missense variant has been observed in affected individual(s) (PMID: 29995633; 28971021; 28498829; 27329734; 25174816) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (CN_hydrolase) - PM1. The variant is present at low allele frequencies population databases (rs13073139 - gnomAD 0.003485%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Ala151Thr) was detected in trans with a pathogenic variant (PMID: 29995633; 28971021; 28498829; 27329734; 25174816) - PM3_very strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. The variant was observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern - BP2. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversitySep 13, 2018- -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Dec 26, 2019NM_000060.2(BTD):c.511G>A(A171T) is classified as pathogenic in the context of biotinidase deficiency. Please note that this variant is frequently observed in combination with D444H in the literature, which suggests they are likely to be on the same chromosome. When A171T and D444H are present on the same chromosome, this combination of variants is associated with profound biotinidase deficiency. Sources cited for classification include the following: PMID 27625817, 29995633, 28971021, 21752405 and 18845537. Classification of NM_000060.2(BTD):c.511G>A(A171T) 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. -
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJul 05, 2018This sequence change replaces alanine with threonine at codon 171 of the BTD protein (p.Ala171Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs13073139, ExAC 0.07%). This variant has been reported in the literature in multiple individuals affected with biotinidase (BTD) deficiency co-occurring on the same chromosome with the common pathogenic p.Asp444His BTD variant (PMID: 10206677, 21752405, 9654207, 20556795, 12227467, 25174816, 20549359, 27329734, 9375914). ClinVar contains an entry for this variant (Variation ID: 25016, 38298). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. Therefore, it has been classified as a Variant of Uncertain Significance. -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 31, 2017The p.Ala171Thr (NM_000060.2 c.511G>A) variant in BTD has previously been reported in several compound heterozygous individuals with biotinidase deficiency (Norrgard 1998 and Borsatto 2014). These reports identify the variant in cis with p.Asp444His (c.1330G>C), a partial deficiency allele on its own. The p.Ala171Thr variant has been identified in 0.04% (47/120,592) of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs13073139), which is assumed to represent the combined p.[Ala171Thr;Asp444His] allele. In summary, the p.Ala171Thr variant, when found as p.[Ala171Thr;Asp444His], meets our criteria to be classified as pathogenic for biotinidase deficiency in an autosomal recessive manner primarily based upon its occurrence in trans with other pathogenic variants in affected individuals. -
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityMar 02, 2023- -
not provided, no classification providedphenotyping onlyGenomeConnect, ClinGen-Variant interpretted as Pathogenic and reported on 12-12-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 18, 2017- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 29, 2022Variant summary: BTD c.451G>A (p.Ala151Thr) results in a non-conservative amino acid change located in the Carbon-nitrogen hydrolase (IPR003010) 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 0.00033 in 251332 control chromosomes (gnomAD), predominantly at a frequency of 0.00065 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BTD causing Biotinidase Deficiency (0.00033 vs 0.0046), allowing no conclusion about variant significance. c.451G>A (often reported as c.511G>A) frequently occurs in cis with c.1270G>C [p.Asp424His] (often reported as c.1330G>C, p.Asp444His) as a complex allele. This allele has been reported in the literature in multiple individuals affected with Biotinidase Deficiency (e.g.Pomponio_2000, Borsatto_2019, Sarafoglou_2009, Tangeraas_2020). These data indicate that the variant is very likely to be associated with disease. Although the variant has not been examined in vitro in isolation, the complex allele is expected to have 0-10% enzymatic activity based on plasma biotinidase activity levels from patients whose other allele has a quantified variant (Borsatto_2019). Twelve ClinVar submitters have assessed the variant since 2014: eleven have classified the variant as pathogenic and one as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 25, 2022- -
not provided, no classification providedliterature onlyGeneReviews-- -
not provided Pathogenic:7
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2018- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsAug 13, 2014- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenNov 03, 2021- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxSep 13, 2018The A171T variant has only been reported on the same allele as D444H comprising what has been described as a double mutation allele, denoted A171T;D444H. A171T;D444H has been observed in approximately 17% of alleles in children with profound biotinidase deficiency ascertained by newborn screening in the United States (Norrgard et al., 1999). The A171T variant was seen with the D444H variant at GeneDx. -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJan 07, 2021- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsSep 29, 2021The c.511G>A (p.A171T) 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 511, causing the alanine (A) at amino acid position 171 to be replaced by a threonine (T). Manual RD edits for complex allele_x000D_ _x000D_ _x000D_ The c.1330G>C (p.D444H) alteration is located in exon 4 (coding exon 4) of the BTD gene. This alteration results from a G to C substitution at nucleotide position 1330, causing the aspartic acid (D) at amino acid position 444 to be replaced by a histidine (H). The c.511G>A (p.A171T) 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 511, causing the alanine (A) at amino acid position 171 to be replaced by a threonine (T)._x000D_ _x000D_ The [c.1330G>C (p.D444H); c.511G>A (p.A171T)] complex allele results in a profound deficiency allele with <10% of residual enzyme activity. This complex allele has been reported in patients with profound biotinidase deficiency when in trans with another profound allele or in the homozygous state (Swango, 1998; Norrgard, 1998; Mil&aacute;nkovics, 2010; Cowan, 2010)._x000D_ _x000D_ Based on the available evidence, the BTD [c.1330G>C (p.D444H); c.511G>A (p.A171T)] complex allele is classified as pathogenic. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.28
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Pathogenic
0.45
Cadd
Pathogenic
29
Dann
Pathogenic
1.0
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
1.0
D
M_CAP
Uncertain
0.16
D
MetaRNN
Pathogenic
0.79
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.84
D
MutationTaster
Benign
1.0
A;A;A;A
PrimateAI
Uncertain
0.68
T
Polyphen
1.0
.;.;D;.;.;.;.;.
Vest4
0.91, 0.90, 0.88
MVP
1.0
MPC
0.42
ClinPred
0.82
D
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.92
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs13073139; hg19: chr3-15685874; API