3-15641990-TC-T

Variant names:

• chr3-15641990-TC-T
• rs397514356
• NM_001370658.1:c.333delC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001370658.1(BTD):​c.333delC​(p.Phe111LeufsTer28) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BTD NM_001370658.1 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.161
• Publications: 2 publications found

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]

BTD Gene-Disease associations (from GenCC):

• biotinidase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, ClinGen, Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-15641990-TC-T is Pathogenic according to our data. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15641990-TC-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 587746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTD	NM_001370658.1	c.333delC	p.Phe111LeufsTer28	frameshift_variant	Exon 3 of 4	ENST00000643237.3	NP_001357587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTD	ENST00000643237.3	c.333delC	p.Phe111LeufsTer28	frameshift_variant	Exon 3 of 4		NM_001370658.1	ENSP00000495254.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Biotinidase deficiency Pathogenic:2

May 15, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jun 12, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation, as the last 413 amino acids are replaced with 27 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35032046, 12359137, 31973013) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.16
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397514356; hg19: chr3-15683497;