rs397514369

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

Scores

14
4
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 9.98
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]

Genome browser will be placed here

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
BTDNM_001370658.1 linkuse as main transcriptc.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
BTDENST00000643237.3 linkuse as main transcriptc.497G>A p.Cys166Tyr missense_variant 4/4 NM_001370658.1 ENSP00000495254 P1P43251-4

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251430
Hom.:
1
AF XY:
0.0000294
AC XY:
4
AN XY:
135874
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000103
AC:
15
AN:
1461890
Hom.:
1
Cov.:
31
AF XY:
0.0000124
AC XY:
9
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000128
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
31
Alfa
AF:
0.00152
Hom.:
0
ExAC
AF:
0.0000247
AC:
3

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 03, 2024This 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 providedclinical testingCounsylJul 11, 2019- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineNov 03, 2022The 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 submitterclinical testingBaylor GeneticsMar 20, 2024- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Aug 06, 2020- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 23, 2023Variant 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 submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 25, 2024- -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Dec 11, 2012- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.88
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
29
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.68
.;.;D;.;.;.;D;.
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.97
.;D;D;.;.;D;D;D
M_CAP
Pathogenic
0.43
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.5
.;.;M;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-10
.;D;.;.;.;D;D;D
REVEL
Pathogenic
0.89
Sift
Pathogenic
0.0
.;D;.;.;.;D;D;D
Sift4G
Pathogenic
0.0
.;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
0.99
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.99
gMVP
0.99

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: rs397514369; hg19: chr3-15685920; API