rs145388314

Positions:

• chr3-15644501-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6 BP7 BS2_Supporting

The NM_001370658.1(BTD):​c.585C>T​(p.Leu195=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00869 in 1,614,172 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0066 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0089 (68 hom.)
• Consequence: BTD NM_001370658.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -0.899

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 3-15644501-C-T is Benign according to our data. Variant chr3-15644501-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 25032.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1, Likely_benign=1}. Variant chr3-15644501-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.899 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 6 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	c.585C>T	p.Leu195=	synonymous_variant	4/4	ENST00000643237.3	NP_001357587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BTD	ENST00000643237.3	c.585C>T	p.Leu195=	synonymous_variant	4/4		NM_001370658.1	ENSP00000495254	P1

Frequencies

GnomAD3 genomes AF: 0.00661 AC: 1006 AN: 152162 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00413

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00735

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00997

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00798 AC: 2006 AN: 251478 Hom.: 12 AF XY: 0.00797 AC XY: 1083 AN XY: 135910

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00358

Gnomad ASJ exome AF: 0.0332

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.00841

Gnomad NFE exome AF: 0.0111

Gnomad OTH exome AF: 0.00928

GnomAD4 exome AF: 0.00891 AC: 13021 AN: 1461892 Hom.: 68 Cov.: 31 AF XY: 0.00874 AC XY: 6354 AN XY: 727248

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00371

Gnomad4 ASJ exome AF: 0.0335

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00128

Gnomad4 FIN exome AF: 0.00754

Gnomad4 NFE exome AF: 0.00976

Gnomad4 OTH exome AF: 0.00876

GnomAD4 genome AF: 0.00661 AC: 1006 AN: 152280 Hom.: 6 Cov.: 31 AF XY: 0.00616 AC XY: 459 AN XY: 74472

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.0317

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00735

Gnomad4 NFE AF: 0.00997

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.0105 Hom.: 6

Bravo AF: 0.00676

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0131

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Biotinidase deficiency Uncertain:1 Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 02, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 01, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2015	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. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	BTD: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 06, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	2.1
DANN	Benign	0.73

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: rs145388314; hg19: chr3-15686008;