rs35034250

Positions:

chr3-15645027-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBS1BS2_Supporting

The NM_001370658.1(BTD):c.1111C>T(p.Pro371Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,614,166 control chromosomes in the GnomAD database, including 431 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 30 hom., cov: 32)

Exomes 𝑓: 0.022 ( 401 hom. )

Consequence

BTD
NM_001370658.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.172

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 -17 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031863153).

BP6

Variant 3-15645027-C-T is Benign according to our data. Variant chr3-15645027-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 38570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15645027-C-T is described in Lovd as [Pathogenic]. Variant chr3-15645027-C-T is described in Lovd as [Benign]. Variant chr3-15645027-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.015 (2289/152286) while in subpopulation NFE AF= 0.0251 (1709/68018). AF 95% confidence interval is 0.0241. There are 30 homozygotes in gnomad4. There are 1039 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 30 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.1111C>T	p.Pro371Ser	missense_variant	4/4	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.1111C>T	p.Pro371Ser	missense_variant	4/4		NM_001370658.1	ENSP00000495254	P1	P43251-4

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2287

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00499

Gnomad AMI

AF:

0.00769

Gnomad AMR

AF:

0.0114

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00622

Gnomad FIN

AF:

0.0118

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0251

Gnomad OTH

AF:

0.00908

GnomAD3 exomes

AF:

0.0139

AC:

3500

AN:

251428

Hom.:

AF XY:

0.0140

AC XY:

1903

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00474

Gnomad AMR exome

AF:

0.00546

Gnomad ASJ exome

AF:

0.00456

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00532

Gnomad FIN exome

AF:

0.0108

Gnomad NFE exome

AF:

0.0238

Gnomad OTH exome

AF:

0.0132

GnomAD4 exome

AF:

0.0219

AC:

32039

AN:

1461880

Hom.:

401

Cov.:

AF XY:

0.0211

AC XY:

15346

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00391

Gnomad4 AMR exome

AF:

0.00635

Gnomad4 ASJ exome

AF:

0.00436

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00511

Gnomad4 FIN exome

AF:

0.0112

Gnomad4 NFE exome

AF:

0.0263

Gnomad4 OTH exome

AF:

0.0202

GnomAD4 genome

AF:

0.0150

AC:

2289

AN:

152286

Hom.:

Cov.:

AF XY:

0.0140

AC XY:

1039

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00498

Gnomad4 AMR

AF:

0.0114

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00643

Gnomad4 FIN

AF:

0.0118

Gnomad4 NFE

AF:

0.0251

Gnomad4 OTH

AF:

0.00899

Alfa

AF:

0.0216

Hom.:

Bravo

AF:

0.0147

TwinsUK

AF:

0.0237

AC:

ALSPAC

AF:

0.0280

AC:

108

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.0241

AC:

207

ExAC

AF:

0.0140

AC:

1698

EpiCase

AF:

0.0239

EpiControl

AF:

0.0204

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 26, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 22, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

Biotinidase deficiency

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 04, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 12, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	BTD: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

6.7

DANN

Benign

0.43

DEOGEN2

Benign

0.29

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

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.63

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

MetaRNN

Benign

0.0032

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

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.3

.;.;L;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.63

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

REVEL

Benign

0.16

Sift

Benign

0.26

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

Sift4G

Benign

0.45

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

Polyphen

0.0020

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

Vest4

0.064, 0.031, 0.041

MPC

0.072

ClinPred

0.0015

GERP RS

2.2

Varity_R

0.023

gMVP

0.50

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