3-15644736-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 3P and 17B. PM1PP2BP4_StrongBP6_Very_StrongBS1BS2_Supporting

The NM_001370658.1(BTD):c.820A>G(p.Ile274Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,614,190 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 40 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 34 hom. )

Consequence

BTD
NM_001370658.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.0220

Publications

8 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 -14 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001370658.1

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=0.006632507).

BP6

Variant 3-15644736-A-G is Benign according to our data. Variant chr3-15644736-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 25047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0109 (1663/152296) while in subpopulation AFR AF = 0.0384 (1594/41558). AF 95% confidence interval is 0.0368. There are 40 homozygotes in GnomAd4. There are 794 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 40 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.820A>G	p.Ile274Val	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.820A>G	p.Ile274Val	missense_variant	Exon 4 of 4		NM_001370658.1	ENSP00000495254.2		P43251-4

Frequencies

GnomAD3 genomes

AF:

0.0109

AC:

1654

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0383

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

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:

0.0000441

Gnomad OTH

AF:

0.00527

GnomAD2 exomes

AF:

0.00324

AC:

814

AN:

251404

AF XY:

0.00230

show subpopulations

Gnomad AFR exome

AF:

0.0423

Gnomad AMR exome

AF:

0.00298

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.00123

AC:

1796

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

767

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0422

AC:

1412

AN:

33480

American (AMR)

AF:

0.00320

AC:

143

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000209

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000504

AC:

AN:

1112012

Other (OTH)

AF:

0.00248

AC:

150

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

128

256

385

513

641

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.0109

AC:

1663

AN:

152296

Hom.:

Cov.:

AF XY:

0.0107

AC XY:

794

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0384

AC:

1594

AN:

41558

American (AMR)

AF:

0.00359

AC:

AN:

15302

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:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68026

Other (OTH)

AF:

0.00521

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

162

243

324

405

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:

0.00470

Hom.:

Bravo

AF:

0.0129

ESP6500AA

AF:

0.0395

AC:

174

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00396

AC:

481

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Biotinidase deficiency

Benign:7

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 18, 2021

Pars Genome Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 30, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 06, 2018

Counsyl

Significance:Likely benign

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. -

not provided

Benign:4

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BTD: BP4, BS1, BS2 -

Sep 28, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 30, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

BTD-related disorder

Benign:1

Feb 20, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

not specified

Benign:1

May 17, 2022

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BTD c.820A>G (p.Ile274Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0032 in 251404 control chromosomes, predominantly at a frequency of 0.042 within the African or African-American subpopulation in the gnomAD database, including 15 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 9.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in BTD causing Biotinidase Deficiency phenotype (0.0046), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.018

(source)

DANN

Benign

0.21

DEOGEN2

Benign

0.27

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

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0063

LIST_S2

Benign

0.60

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

MetaRNN

Benign

0.0066

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

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.1

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

PhyloP100

-0.022

PrimateAI

Benign

0.26

PROVEAN

Benign

0.64

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

REVEL

Uncertain

0.32

Sift

Benign

1.0

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

Sift4G

Benign

1.0

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

Polyphen

0.0

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

Vest4

0.049, 0.030, 0.032

MVP

0.50

MPC

0.061

ClinPred

0.0019

GERP RS

-4.3

Varity_R

0.016

gMVP

0.67

Mutation Taster

=83/17

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