3-15645485-C-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PM1PM5PP2PP5_Very_StrongBP4

The NM_001370658.1(BTD):c.1569C>A(p.Asp523Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000033 in 1,605,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D523V) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

BTD
NM_001370658.1 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 1.01

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

biotinidase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, ClinGen, Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

BTD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_001370658.1

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-15645484-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2503972.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 88 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: -0.52516 (below the threshold of 3.09). Trascript score misZ: 0.15371 (below the threshold of 3.09). GenCC associations: The gene is linked to Leigh syndrome, biotinidase deficiency.

PP5

Variant 3-15645485-C-A is Pathogenic according to our data. Variant chr3-15645485-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 25103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.3992411). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTD	NM_001370658.1 link	c.1569C>A	p.Asp523Glu	missense_variant	Exon 4 of 4	ENST00000643237.3	NP_001357587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTD	ENST00000643237.3 link	c.1569C>A	p.Asp523Glu	missense_variant	Exon 4 of 4		NM_001370658.1	ENSP00000495254.2

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000592

AC:

AN:

236452

AF XY:

0.0000463

show subpopulations

Gnomad AFR exome

AF:

0.000824

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1452898

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

722982

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111944

Other (OTH)

AF:

0.0000331

AC:

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000204

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.000700

AC:

AN:

41418

American (AMR)

AF:

0.000131

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000547

Hom.:

Bravo

AF:

0.000204

ESP6500AA

AF:

0.000464

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000828

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Biotinidase deficiency

Pathogenic:7

May 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 30, 2024

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 30, 2018

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 22, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2020

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS4, PM2, PM3, PP2 -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 543 of the BTD protein (p.Asp543Glu). This variant is present in population databases (rs146136265, gnomAD 0.06%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 25174816, 25967232, 28498829). ClinVar contains an entry for this variant (Variation ID: 25103). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

May 28, 2019

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:3

Jul 21, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as D543E; This variant is associated with the following publications: (PMID: 26810761, 25174816, 25967232, 22698809, 28498829, 35167647, 31801038) -

Jan 03, 2018

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 24, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

.;.;D;.;.;.;.

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.75

.;T;T;.;.;T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.40

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

MetaSVM

Uncertain

0.45

MutationAssessor

Uncertain

2.8

.;.;M;.;.;.;.

PhyloP100

1.0

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.6

.;D;.;.;.;D;D

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0010

.;D;.;.;.;D;D

Sift4G

Pathogenic

0.0

.;D;.;.;.;D;D

Polyphen

0.99

.;.;D;.;.;.;.

Vest4

0.60, 0.60, 0.56

MutPred

0.66

.;.;Gain of disorder (P = 0.1419);.;.;.;.;

MVP

0.66

MPC

0.34

ClinPred

0.63

GERP RS

-1.2

Varity_R

0.56

gMVP

0.77

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over