rs34885143

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 1P and 10B. PP2BP4_StrongBP6BS1BS2_Supporting

The NM_001370658.1(BTD):c.73G>A(p.Gly25Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,614,134 control chromosomes in the GnomAD database, including 169 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.010 ( 13 hom., cov: 32)

Exomes 𝑓: 0.014 ( 156 hom. )

Consequence

BTD
NM_001370658.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:10

Conservation

PhyloP100: -0.0140

Publications

11 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: Benign. The variant received -9 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.005297005).

BP6

Variant 3-15635512-G-A is Benign according to our data. Variant chr3-15635512-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 24973.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.014 (20455/1461890) while in subpopulation NFE AF = 0.0161 (17863/1112008). AF 95% confidence interval is 0.0159. There are 156 homozygotes in GnomAdExome4. There are 9951 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 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.73G>A	p.Gly25Arg	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.73G>A	p.Gly25Arg	missense_variant	Exon 2 of 4		NM_001370658.1	ENSP00000495254.2		P43251-4

Frequencies

GnomAD3 genomes

AF:

0.0101

AC:

1534

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00234

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00439

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.0274

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0155

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.0102

AC:

2560

AN:

251422

AF XY:

0.0101

show subpopulations

Gnomad AFR exome

AF:

0.00240

Gnomad AMR exome

AF:

0.00353

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0240

Gnomad NFE exome

AF:

0.0148

Gnomad OTH exome

AF:

0.0108

GnomAD4 exome

AF:

0.0140

AC:

20455

AN:

1461890

Hom.:

156

Cov.:

AF XY:

0.0137

AC XY:

9951

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00206

AC:

AN:

33480

American (AMR)

AF:

0.00373

AC:

167

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000306

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.00435

AC:

375

AN:

86258

European-Finnish (FIN)

AF:

0.0246

AC:

1316

AN:

53420

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0161

AC:

17863

AN:

1112008

Other (OTH)

AF:

0.0106

AC:

639

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1314

2628

3943

5257

6571

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

664

1328

1992

2656

3320

<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:

0.0101

AC:

1535

AN:

152244

Hom.:

Cov.:

AF XY:

0.00997

AC XY:

742

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00233

AC:

AN:

41550

American (AMR)

AF:

0.00438

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5172

South Asian (SAS)

AF:

0.00311

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0274

AC:

291

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0155

AC:

1052

AN:

68008

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

149

223

298

372

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0135

Hom.:

Bravo

AF:

0.00868

TwinsUK

AF:

0.0135

AC:

ALSPAC

AF:

0.0148

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0159

AC:

137

ExAC

AF:

0.00995

AC:

1208

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0134

EpiControl

AF:

0.0122

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Biotinidase deficiency

Uncertain:1Benign:5

Jun 23, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Apr 01, 2020

Elsea Laboratory, Baylor College of Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

European Non-Finnish population allele frequency is 1.469% (rs34885143, 1052/69016 alleles, 11 homozygotes in gnomAD v3.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.4.0, this variant is classified as BENIGN. Following criteria are met: BA1 -

May 18, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:3

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BTD: BP4, BS1, BS2 -

Nov 21, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 03, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26361991, 12359137, 27329734, 25087612, 21228398, 10400129, 15060693, 15776412, 11668630, 26810761, 16150625, 26990548, 27657684, 31664448) -

May 04, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:1

Feb 08, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 18, 2022

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

BTD-related disorder

Benign:1

Jan 03, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.13

CADD

Benign

1.6

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.26

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

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.60

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

MetaRNN

Benign

0.0053

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

MetaSVM

Benign

-0.40

MutationAssessor

Benign

0.69

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

PhyloP100

-0.014

PrimateAI

Benign

0.22

PROVEAN

Pathogenic

-5.0

D;N;.;.;.;.;N;N;N;.

REVEL

Uncertain

0.43

Sift

Benign

0.11

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

Sift4G

Benign

0.43

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

Polyphen

0.0010

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

Vest4

0.15, 0.15, 0.16

MutPred

0.74

.;.;Gain of phosphorylation at S48 (P = 0.0901);.;Gain of phosphorylation at S48 (P = 0.0901);.;.;.;.;.;

MPC

0.084

ClinPred

0.013

GERP RS

-0.69

PromoterAI

0.015

Neutral

(source)

Varity_R

0.032

gMVP

0.36

Mutation Taster

=81/19

polymorphism

(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