rs397514333

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The NM_001370658.1(BTD):c.152T>C(p.Leu51Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000688 in 1,614,216 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 25 hom. )

Consequence

BTD
NM_001370658.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.01

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0107168555).

BS2

High Homozygotes in GnomAdExome4 at 25 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTD	NM_001370658.1 link	c.152T>C	p.Leu51Pro	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.152T>C	p.Leu51Pro	missense_variant	Exon 2 of 4		NM_001370658.1	ENSP00000495254.2		P43251-4

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152204

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:

0.00890

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00154

AC:

386

AN:

251432

Hom.:

AF XY:

0.00216

AC XY:

294

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0124

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000731

AC:

1068

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

811

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0120

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.000397

GnomAD4 genome

AF:

0.000276

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00870

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000353

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.00159

AC:

193

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Biotinidase deficiency

Benign:4

Apr 20, 2018

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 14, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Leu71Pro variant in BTD has been identified in the compound heterozygous state, in trans with a frameshift variant and in cis with a rare missense variant, in an individual from Hungary with biotinidase deficiency (PMID: 14707518). This variant has also been identified in >1% of South Asian chromosomes and 8 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive biotinidase deficiency. -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1Benign:1

Nov 09, 2016

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 12, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.038

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

1.3

DANN

Benign

0.45

DEOGEN2

Benign

0.23

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

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.22

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

MetaRNN

Benign

0.011

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

MetaSVM

Benign

-0.67

MutationAssessor

Benign

-0.79

.;.;N;.;.;.;.;.;.;.

PrimateAI

Benign

0.33

PROVEAN

Benign

0.48

N;N;.;.;.;.;N;N;N;.

REVEL

Uncertain

0.43

Sift

Benign

0.42

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

Sift4G

Benign

0.12

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

Polyphen

0.0

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

Vest4

0.17, 0.17, 0.17

MutPred

0.84

.;.;Gain of sheet (P = 0.0028);.;Gain of sheet (P = 0.0028);.;.;.;.;.;

MVP

0.76

MPC

0.11

ClinPred

0.014

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.036

gMVP

0.74

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