chr3-15635636-T-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The NM_001370658.1(BTD):c.197T>G(p.Met66Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,614,088 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M66V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

BTD
NM_001370658.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 6.99

Publications

1 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 10 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001370658.1

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.942

PP5

Variant 3-15635636-T-G is Pathogenic according to our data. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000. Variant chr3-15635636-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156000.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTD	NM_001370658.1 link	c.197T>G	p.Met66Arg	missense_variant	Exon 2 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.197T>G	p.Met66Arg	missense_variant	Exon 2 of 4		NM_001370658.1	ENSP00000495254.2		P43251-4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251402

AF XY:

0.00000736

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

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:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000629

AC:

AN:

1112012

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000508

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Biotinidase deficiency

Pathogenic:3

Jul 03, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Molecular Genetics Diagnostic Laboratory, Detroit Medical Center University Laboratories

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 86 of the BTD protein (p.Met86Arg). This variant is present in population databases (rs587783002, gnomAD 0.0009%). This missense change has been observed in individual(s) with partial biotinidase deficiency (PMID: 24797656, 25144890, 26361991). 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: 156000). 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 specified

Uncertain:1

Jul 18, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BTD c.197T>G (p.Met66Arg) 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 4e-06 in 251402 control chromosomes (gnomAD). c.197T>G has been reported in the literature in individuals affected with Partial Biotinidase Deficiency (examples: Li_2014, Jay_2015 and Gannavarapu_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26361991, 25144890, 24797656). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.86

.;.;D;.;.;.;.;T;.;.

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

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

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Uncertain

2.8

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

PhyloP100

7.0

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.5

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

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.92, 0.91, 0.92

MutPred

0.77

.;.;Gain of disorder (P = 0.0857);.;Gain of disorder (P = 0.0857);.;.;.;.;.;

MVP

0.99

MPC

0.49

ClinPred

1.0

GERP RS

4.7

PromoterAI

-0.0062

Neutral

(source)

Varity_R

0.99

gMVP

0.99

Mutation Taster

=0/100

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