rs397514333

chr3-15635591-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The NM_001370658.1(BTD):c.152T>C(p.Leu51Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000688 in 1,614,216 control chromosomes in the GnomAD database, including 25 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 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (25 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 2.01

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 Likely_benign. Variant got -6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_001370658.1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0107168555).
• BS2: High Homozygotes in GnomAdExome at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTD	NM_001370658.1	c.152T>C	p.Leu51Pro	missense_variant	2/4	ENST00000643237.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTD	ENST00000643237.3	c.152T>C	p.Leu51Pro	missense_variant	2/4		NM_001370658.1	P1

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00154 AC: 386 AN: 251432 Hom.: 12 AF XY: 0.00216 AC XY: 294 AN XY: 135886

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0124

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000731 AC: 1068 AN: 1461894 Hom.: 25 Cov.: 32 AF XY: 0.00112 AC XY: 811 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74474

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00870

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000353 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.00159 AC: 193

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Biotinidase deficiency Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 14, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Apr 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -
Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Leu71Pro variant in BTD has been identified in the compound heterozygous state, in trans with a frameshift variant and in cis with a rare missense variant, in an individual from Hungary with biotinidase deficiency (PMID: 14707518). This variant has also been identified in >1% of South Asian chromosomes and 8 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive biotinidase deficiency. -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2016	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 12, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.038
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	1.3
Dann	Benign	0.45
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.051	N
MetaRNN	Benign	0.011	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.48	N;N;.;.;.;.;N;N;N;.
REVEL	Uncertain	0.43
Sift	Benign	0.42	T;T;.;.;.;.;T;T;T;.
Sift4G	Benign	0.12	T;T;.;.;.;.;T;T;T;.
Polyphen		0.0	.;.;B;.;.;.;.;.;.;.
Vest4		0.17, 0.17, 0.17
MutPred		0.84		.;.;Gain of sheet (P = 0.0028);.;Gain of sheet (P = 0.0028);.;.;.;.;.;
MVP		0.76
MPC		0.11
ClinPred		0.014	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.74

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: rs397514333; hg19: chr3-15677098; COSMIC: COSV100329821; COSMIC: COSV100329821;