rs146015592

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong

The NM_001370658.1(BTD):c.410G>A(p.Arg137His) variant causes a missense change. The variant allele was found at a frequency of 0.000208 in 1,613,628 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R137C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

BTD
NM_001370658.1 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 4.28

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]

BTD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 0 benign, 3 uncertain in NM_001370658.1

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-15644325-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 25012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 3-15644326-G-A is Pathogenic according to our data. Variant chr3-15644326-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 38290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644326-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTD	NM_001370658.1 linkuse as main transcript	c.410G>A	p.Arg137His	missense_variant	4/4	ENST00000643237.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTD	ENST00000643237.3 linkuse as main transcript	c.410G>A	p.Arg137His	missense_variant	4/4		NM_001370658.1	P1	P43251-4

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

151918

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000108

AC:

AN:

250768

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135574

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000214

AC:

313

AN:

1461710

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

147

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000249

Gnomad4 OTH exome

AF:

0.000513

GnomAD4 genome

AF:

0.000151

AC:

AN:

151918

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74174

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000180

Hom.:

Bravo

AF:

0.000113

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Biotinidase deficiency

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.410G>A;p.(Arg137His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 38290; PMID: 27329734; 26361991; 25754625; 23644139; 22698809; 20224900; 11313766) - PS4.The variant is located in a mutational hot spot and/or critical and well-established functional domain (CN_hydrolase domain) - PM1. The variant is present at low allele frequencies population databases (rs146015592– gnomAD 0.001514%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg137His) was detected in trans with a pathogenic variant (PMID: 27329734; 26361991; 25754625; 23644139; 22698809; 20224900; 11313766) - PM3_strong. Pathogenic missense variant in this residue have been reported (Clinvar ID: 25012) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 24, 2019	NM_000060.2(BTD):c.470G>A(R157H) is classified as pathogenic in the context of biotinidase deficiency. Please note that R157H is seen in patients with both partial and profound biotinidase deficiency. Sources cited for classification include the following: PMID 23644139, 11313766, 16435182, 25754625, 9396567, 27329734 and 26361991. Classification of NM_000060.2(BTD):c.470G>A(R157H) 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 31, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 157 of the BTD protein (p.Arg157His). This variant is present in population databases (rs146015592, gnomAD 0.02%). This missense change has been observed in individual(s) with biotinidase deficicency (PMID: 9396567, 11313766, 20224900, 22698809). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 38290). 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. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 26, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 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, 25423671, 26361991, 27657684, 33123633, 32440248, 33189081, 9396567, 23644139, 25754625, 34426522) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 16, 2022	In the published literature, this variant has reported as one of the most common pathogenic variants associated with biotinidase deficiency in Turkish population (PMIDs: 25754625 (2015), 29353266 (2018), and 33189081 (2021)). This variant has been identified in homozygous state or compound heterozygous state with other pathogenic BTD variants in multiple individuals with profound to partial biotinidase deficiency (PMIDs: 9396567 (1997), 10801053 (2000), 11313766 (2001), 16435182 (2005), 22698809 (2012), 25754625 (2015), 27329734, (2016), 29353266 (2018), and 33189081 (2021)). Therefore, this individual is at least a carrier of biotinidase deficiency. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.083

BayesDel_noAF

Pathogenic

0.17

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.97

M_CAP

Benign

0.066

MetaRNN

Uncertain

0.45

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.10

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.44

Polyphen

0.18

.;.;B;.;.;.;.;.

Vest4

0.58, 0.70, 0.62

MVP

0.94

MPC

0.12

ClinPred

0.075

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.56

gMVP

0.83

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over