rs397514416

Positions:

• chr3-15645170-T-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001370658.1(BTD):​c.1254T>A​(p.Tyr418*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BTD NM_001370658.1 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.983

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 32 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-15645170-T-A is Pathogenic according to our data. Variant chr3-15645170-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 25080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15645170-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTD	NM_001370658.1	c.1254T>A	p.Tyr418*	stop_gained	4/4	ENST00000643237.3	NP_001357587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BTD	ENST00000643237.3	c.1254T>A	p.Tyr418*	stop_gained	4/4		NM_001370658.1	ENSP00000495254.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Biotinidase deficiency Pathogenic:3

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Nov 14, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 11, 2023	This sequence change creates a premature translational stop signal (p.Tyr438*) in the BTD gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 106 amino acid(s) of the BTD protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with biotinidase deficiency (PMID: 15060693, 30912303). ClinVar contains an entry for this variant (Variation ID: 25080). This variant disrupts a region of the BTD protein in which other variant(s) (p.His485Gln) have been determined to be pathogenic (PMID: 25967232, 26810761, 30912303; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 04, 2022

Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 106 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 30912303, 15060693) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Benign	0.088
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.38	N
Vest4		0.80, 0.85, 0.86
GERP RS		-2.5

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: rs397514416; hg19: chr3-15686677;