rs146136265

chr3-15645485-C-Achr3-15645485-C-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1 PM2 PM5 PP5_Very_Strong BP4

The NM_001370658.1(BTD):c.1569C>A(p.Asp523Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000033 in 1,605,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D523G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 1.01

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 Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_001370658.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-15645484-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 800903.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP5: Variant 3-15645485-C-A is Pathogenic according to our data. Variant chr3-15645485-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 25103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15645485-C-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.3992411).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTD	NM_001370658.1	c.1569C>A	p.Asp523Glu	missense_variant	4/4	ENST00000643237.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTD	ENST00000643237.3	c.1569C>A	p.Asp523Glu	missense_variant	4/4		NM_001370658.1	P1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000592 AC: 14 AN: 236452 Hom.: 0 AF XY: 0.0000463 AC XY: 6 AN XY: 129660

Gnomad AFR exome AF: 0.000824

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1452898 Hom.: 0 Cov.: 31 AF XY: 0.0000207 AC XY: 15 AN XY: 722982

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74298

Gnomad4 AFR AF: 0.000700

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000204

ESP6500AA AF: 0.000464 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000828 AC: 10

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Biotinidase deficiency Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 20, 2022	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 30, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 543 of the BTD protein (p.Asp543Glu). This variant is present in population databases (rs146136265, gnomAD 0.06%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 25174816, 25967232, 28498829). ClinVar contains an entry for this variant (Variation ID: 25103). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BTD protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Mar 03, 2020	ACMG classification criteria: PS4, PM2, PM3, PP2 -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as D543E; This variant is associated with the following publications: (PMID: 25967232, 26810761, 25174816, 22698809, 28498829, 35167647, 31801038) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 24, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 03, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.45	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.48	T
Polyphen		0.99	.;.;D;.;.;.;.
Vest4		0.60, 0.60, 0.56
MutPred		0.66		.;.;Gain of disorder (P = 0.1419);.;.;.;.;
MVP		0.66
MPC		0.34
ClinPred		0.63	D
GERP RS		-1.2
Varity_R		0.56
gMVP		0.77

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: rs146136265; hg19: chr3-15686992;