3-15645082-GGGGAAAGGAAGGCTA-GTTCCAATGGCC

Position:

• chr3-15645082-GGGGAAAGGAAGGCTA-GTTCCAATGGCC

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.1167_1181delinsTTCCAATGGCC​(p.Trp389CysfsTer91) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BTD NM_001370658.1 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.75

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 41 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-15645083-GGGAAAGGAAGGCTA-TTCCAATGGCC is Pathogenic according to our data. Variant chr3-15645083-GGGAAAGGAAGGCTA-TTCCAATGGCC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTD	NM_001370658.1	c.1167_1181delinsTTCCAATGGCC	p.Trp389CysfsTer91	frameshift_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.1167_1181delinsTTCCAATGGCC	p.Trp389CysfsTer91	frameshift_variant	4/4		NM_001370658.1	ENSP00000495254	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Biotinidase deficiency Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 21, 2023	This sequence change creates a premature translational stop signal (p.Trp409Cysfs*91) in the BTD gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 135 amino acid(s) of the BTD protein. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with biotinidase deficiency (PMID: 8894703). This variant disrupts a region of the BTD protein in which other variant(s) (p.Leu498Phefs*13) have been determined to be pathogenic (PMID: 17382128, 19728141, 29359854). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 09, 2024	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	May 28, 2014	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 25, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 10, 2021	This frameshift variant causes the premature termination of BTD protein synthesis. In addition, it has been reported in a child with biotinidase deficiency in the published literature (PMID: 8894703 (1996)). Based on the available information, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs672601248; hg19: chr3-15686590;