rs147057169

Positions:

• chr3-15635640-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Moderate BP6 BP7 BS2_Supporting

The NM_001370658.1(BTD):​c.201C>T​(p.Asn67=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,614,200 control chromosomes in the GnomAD database, including 11 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 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (11 hom.)
• Consequence: BTD NM_001370658.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.422

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 3-15635640-C-T is Benign according to our data. Variant chr3-15635640-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 290069.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}. Variant chr3-15635640-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.422 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 11 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.201C>T	p.Asn67=	synonymous_variant	2/4	ENST00000643237.3	NP_001357587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BTD	ENST00000643237.3	c.201C>T	p.Asn67=	synonymous_variant	2/4		NM_001370658.1	ENSP00000495254	P1

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 234 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00247

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00162 AC: 407 AN: 251392 Hom.: 1 AF XY: 0.00172 AC XY: 233 AN XY: 135856

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00208 AC: 3047 AN: 1461894 Hom.: 11 Cov.: 32 AF XY: 0.00204 AC XY: 1480 AN XY: 727248

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000927

Gnomad4 FIN exome AF: 0.00165

Gnomad4 NFE exome AF: 0.00235

Gnomad4 OTH exome AF: 0.00250

GnomAD4 genome AF: 0.00154 AC: 234 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.00153 AC XY: 114 AN XY: 74482

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00247

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00235 Hom.: 2

Bravo AF: 0.00174

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	BTD: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 09, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 08, 2016	- -

Biotinidase deficiency Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.1
DANN	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147057169; hg19: chr3-15677147;