rs104893688

chr3-15645451-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001370658.1(BTD):c.1535C>T(p.Thr512Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,611,856 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T512T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 7.34

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]

ACMG classification

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 1 benign, 2 uncertain in NM_001370658.1
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.857
• PP5: Variant 3-15645451-C-T is Pathogenic according to our data. Variant chr3-15645451-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15645451-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTD	NM_001370658.1	c.1535C>T	p.Thr512Met	missense_variant	4/4	ENST00000643237.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTD	ENST00000643237.3	c.1535C>T	p.Thr512Met	missense_variant	4/4		NM_001370658.1	P1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000693 AC: 17 AN: 245398 Hom.: 0 AF XY: 0.0000825 AC XY: 11 AN XY: 133376

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000870

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: 0.000127

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000117 AC: 171 AN: 1459576 Hom.: 0 Cov.: 31 AF XY: 0.000113 AC XY: 82 AN XY: 726104

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000782

Gnomad4 NFE exome AF: 0.000127

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74462

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000907 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000495 AC: 6

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Biotinidase deficiency Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 532 of the BTD protein (p.Thr532Met). This variant is present in population databases (rs104893688, gnomAD 0.02%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 9654207, 10400129, 10801053, 21752405, 22011816, 22698809, 27657684). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Mediterranean ancestry (PMID: 9654207, 10400129, 10801053, 21752405, 22011816, 22698809, 27657684). ClinVar contains an entry for this variant (Variation ID: 1897). 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	Oct 30, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 13, 2020	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS4,PM1,PM2,PM3,PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 18, 2018	The BTD c.1595C>T; p.Thr532Met variant (rs104893688), is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with partial to profound biotinidase deficiency (Cowan 2012, Funghini 2002, Laszlo 2003, Norrgard 1999, Ohlsson 2010, Pomponio 2000, Swango 1998, Wiltink 2016, Wolf 2017). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 1897), and is found in the non-Finnish European population with an allele frequency of 0.015% (19/125,971 alleles) in the Genome Aggregation Database. The threonine at codon 532 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Thr532Met variant is considered to be severely 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. Funghini S et al. Two new mutations in children affected by partial biotinidase deficiency ascertained by newborn screening. J Inherit Metab Dis. 2002 Aug;25(4):328-30. Laszlo A et al. Neonatal screening for biotinidase deficiency in Hungary: clinical, biochemical and molecular studies. J Inherit Metab Dis. 2003;26(7):693-8. Norrgard KJ 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 Jul;46(1):20-7. Ohlsson A et al. Profound biotinidase deficiency: a rare disease among native Swedes. J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S175-8. Pomponio RJ et al. Novel mutations cause biotinidase deficiency in Turkish children. J Inherit Metab Dis. 2000 Mar;23(2):120-8. Swango KL et al. Partial biotinidase deficiency is usually due to the D444H mutation in the biotinidase gene. Hum Genet. 1998 May;102(5):571-5. Wiltink RC et al. Neonatal screening for profound biotinidase deficiency in the Netherlands: consequences and considerations. Eur J Hum Genet. 2016 Oct;24(10):1424-9. Wolf B. Successful outcomes of older adolescents and adults with profound biotinidase deficiency identified by newborn screening. Genet Med. 2017 Apr;19(4):396-402. -
Pathogenic, criteria provided, single submitter	literature only	Counsyl	Jun 29, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 20, 2021	Variant summary: BTD c.1535C>T (p.Thr512Met, also known as c.1595C>T/p.Thr532Met in NM_000060) results in a non-conservative amino acid change located 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 6.9e-05 in 245398 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BTD causing Biotinidase Deficiency (6.9e-05 vs 0.0046), allowing no conclusion about variant significance. This variant has been reported in the literature in multiple individuals (both homozygous and compound heterozygous state) affected with partial to profound Biotinidase Deficiency (example: Pomponio_2000, Lara_2015). These data indicate that the variant is very likely to be associated with disease. Less than 10% of mean normal enzymatic activity was seen in serum or plasma of patients who were homozygous for the variant of interest (Pomponio_2000). Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2000	- -
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	MGZ Medical Genetics Center	Jun 17, 2022	- -

not provided Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 10, 2020	The variant found in at least one symptomatic patient. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have phenotype known to be consistent with disease. The variant predicted to have a damaging effect on the protein. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26361991, 26810761, 27657684, 10400129, 26589311, 25754625, 14707518, 25174816, 12227467, 22698809, 9654207, 10801053, 30912303) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	BTD: PM3:Very Strong, PM2, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 21, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.59	T
Polyphen		1.0	.;.;D;.;.;.;.
Vest4		0.95, 0.96, 0.95
MVP		0.93
MPC		0.43
ClinPred		0.90	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.95

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

Other links and lift over

dbSNP: rs104893688; hg19: chr3-15686958; COSMIC: COSV100329741; COSMIC: COSV100329741;