rs34885143

chr3-15635512-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:9
• Conservation: PhyloP100: -0.0140

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]

ACMG classification

Verdict is Benign. Variant got -12 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 GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTD	NM_001370658.1	c.73G>A	p.Gly25Arg	missense_variant	2/4	ENST00000643237.3

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1534 AN: 152126 Hom.: 13 Cov.: 32

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.: 20 AF XY: 0.0101 AC XY: 1379 AN XY: 135880

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.: 32 AF XY: 0.0137 AC XY: 9951 AN XY: 727244

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.: 13 Cov.: 32 AF XY: 0.00997 AC XY: 742 AN XY: 74442

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.: 24

Bravo AF: 0.00868

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.0148 AC: 57

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0159 AC: 137

ExAC AF: 0.00995 AC: 1208

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0134

EpiControl AF: 0.0122

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Biotinidase deficiency Uncertain:1 Benign:4

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 -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 23, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Elsea Laboratory, Baylor College of Medicine	Apr 01, 2020	- -

not provided Uncertain:1 Benign:3

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	Jan 01, 2024	BTD: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 21, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 04, 2017	- -

not specified Uncertain:1 Benign: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, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	1.6
Dann	Benign	0.81
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
MetaRNN	Benign	0.0053	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.40	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.22	T
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	T
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

Other links and lift over

dbSNP: rs34885143; hg19: chr3-15677019;