dbSNP rs13073139: BTD:p.Ala151Thr (chr3-15644367-G-A) – ACMG Classification: Pathogenic (13 pts)

Variant summary

Our verdict is The variant received 13 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2_SupportingPP3_ModeratePP5_Strong

The NM_001370658.1(BTD):c.451G>A (p.Ala151Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000527 (AC=851) in the gnomAD database across 1,613,968 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000644. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 10.00). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (no review stars). ClinVar reports functional evidence for this variant: "SCV005076304: At least one publication reports this complex variant results in expected activity 0-10% based on the biotinidase activity in plasma (e.g. Borsatto_2019). PMID:31337602". This exact variant is curated in the UniProt human variants database as Uncertain Significance.

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00055 ( 0 hom. )

Consequence

BTD
NM_001370658.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:21U:2O:2

Conservation

PhyloP100: 10.0

Publications

45 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: Ambry Genetics, Myriad Women's Health, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Natera, G2P, PanelApp Australia
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

BTD links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001370658.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 points.

PS3

Well-established functional study supports damaging effect (PS3); SCV005076304: At least one publication reports this complex variant results in expected activity 0-10% based on the biotinidase activity in plasma (e.g. Borsatto_2019). PMID:31337602

PM1

Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 2 pathogenic, 0 benign (OR vs. background: 25.0).

PM2

Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000644 — borderline rare for AR gene (threshold 0.001) — PM2 supporting.

PP3

Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).

PP5

ClinVar 0-star pathogenic — supporting (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 0 star(s). ClinVar submissions strongly and reliably favor pathogenicity (19/21 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001370658.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BTD	NM_001370658.1	MANE Select	c.451G>A	p.Ala151Thr	missense	Exon 4 of 4	NP_001357587.1	P43251-4
BTD	NM_001281723.4		c.451G>A	p.Ala151Thr	missense	Exon 4 of 4	NP_001268652.2	P43251-4
BTD	NM_001281724.3		c.451G>A	p.Ala151Thr	missense	Exon 6 of 6	NP_001268653.2	P43251-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BTD	ENST00000643237.3	MANE Select	c.451G>A	p.Ala151Thr	missense	Exon 4 of 4	ENSP00000495254.2	P43251-4
BTD	ENST00000303498.10	TSL:1	c.451G>A	p.Ala151Thr	missense	Exon 5 of 5	ENSP00000306477.6	P43251-4
BTD	ENST00000427382.2	TSL:4	c.451G>A	p.Ala151Thr	missense	Exon 4 of 4	ENSP00000397113.2	P43251-4

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.000603

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000330

AC:

AN:

251332

AF XY:

0.000346

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000651

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000546

AC:

798

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000535

AC XY:

389

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33476

American (AMR)

AF:

0.000157

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:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000684

AC:

761

AN:

1112008

Other (OTH)

AF:

0.000397

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

136

181

226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

150

<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:

0.000348

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41406

American (AMR)

AF:

0.000262

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000603

AC:

AN:

68016

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.000586

Hom.:

Bravo

AF:

0.000404

EpiCase

AF:

0.000491

EpiControl

AF:

0.000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Biotinidase deficiency (17)

not provided (7)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.79

MetaSVM

Pathogenic

0.84

MutationAssessor

Pathogenic

3.5

PhyloP100

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.90

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over