rs397514398

Variant names:

• chr3-15644907-AC-A
• rs397514398
• NM_001370658.1:c.992delC

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.992delC​(p.Thr331LysfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BTD NM_001370658.1 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.0250

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 47 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-15644907-AC-A is Pathogenic according to our data. Variant chr3-15644907-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 25057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644907-AC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTD	NM_001370658.1	c.992delC	p.Thr331LysfsTer12	frameshift_variant	Exon 4 of 4	ENST00000643237.3	NP_001357587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTD	ENST00000643237.3	c.992delC	p.Thr331LysfsTer12	frameshift_variant	Exon 4 of 4		NM_001370658.1	ENSP00000495254.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Biotinidase deficiency Pathogenic:3

Jul 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Thr351Lysfs*12) in the BTD gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 193 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 profound biotinidase deficiency (PMID: 12359137, 15776412, 20083419). ClinVar contains an entry for this variant (Variation ID: 25057). 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. -

May 23, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 09, 2016

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:2

Sep 27, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1052delC variant in the BTD gene has been reported previously in association with biotinidase deficiency (Wolf et al. 2002; Iqbal et al. 2010; Gannavarapu et al. 2015). The c.1052delC variant has been reported to be associated with profound biotinidase deficiency in a patient who also harbored a second frameshift variant as well as in a patient homozygous for c.1052delC (Wolf et al. 2002; Iqbal et al. 2010). However, a second patient homozygous for c.1052delC was reported with partial biotinidase deficiency (Iqbal et al. 2010). The c.1052delC deletion causes a frameshift starting with codon Threonine 351, changes this amino acid to a Lysine residue and creates a premature Stop codon at position 12 of the new reading frame, denoted p.Thr351LysfsX12. This pathogenic variant is predicted to cause loss of normal protein function through protein truncation. The c.1052delC variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, we interpret c.1052delC to be a pathogenic variant. -

Nov 13, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. -

Computational scores

Source: dbNSFP v4.3

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: rs397514398; hg19: chr3-15686414;