rs34885143

Positions:

chr3-15635512-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1BS2_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. 13/20 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 0.010 ( 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:9

Conservation

PhyloP100: -0.0140

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 Benign. Variant got -9 ACMG points.

BP4

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

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome 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 gnomad4_exome. There are 9951 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

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/exons	MANE	Protein	UniProt
BTD	NM_001370658.1 linkuse as main transcript	c.73G>A	p.Gly25Arg	missense_variant	2/4	ENST00000643237.3	NP_001357587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BTD	ENST00000643237.3 linkuse as main transcript	c.73G>A	p.Gly25Arg	missense_variant	2/4		NM_001370658.1	ENSP00000495254	P1	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

GnomAD3 exomes

AF:

0.0102

AC:

2560

AN:

251422

Hom.:

AF XY:

0.0101

AC XY:

1379

AN XY:

135880

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 SAS exome

AF:

0.00418

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

Gnomad4 AFR exome

AF:

0.00206

Gnomad4 AMR exome

AF:

0.00373

Gnomad4 ASJ exome

AF:

0.000306

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00435

Gnomad4 FIN exome

AF:

0.0246

Gnomad4 NFE exome

AF:

0.0161

Gnomad4 OTH exome

AF:

0.0106

GnomAD4 genome

AF:

0.0101

AC:

1535

AN:

152244

Hom.:

Cov.:

AF XY:

0.00997

AC XY:

742

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00233

Gnomad4 AMR

AF:

0.00438

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.0274

Gnomad4 NFE

AF:

0.0155

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.0136

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:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Biotinidase deficiency

Uncertain:1Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Elsea Laboratory, Baylor College of Medicine	Apr 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	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 -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 23, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not provided

Uncertain:1Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 04, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 21, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2021	This variant is associated with the following publications: (PMID: 26361991, 12359137, 27329734, 25087612, 21228398, 10400129, 15060693, 15776412, 11668630, 26810761, 16150625, 26990548, 27657684, 31664448) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	BTD: BP4, BS1, BS2 -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	- -

BTD-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 03, 2024

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

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;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N

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

Varity_R

0.032

gMVP

0.36

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