chr3-15635477-GCGGCTG-TCC

Variant names:

• chr3-15635477-GCGGCTG-TCC
• rs80338684
• NM_001370658.1:c.38_44delGCGGCTGinsTCC

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PVS1 PM2 PP2 PP5_Very_Strong

The NM_001370658.1(BTD):​c.38_44delGCGGCTGinsTCC​(p.Cys13PhefsTer36) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. C13C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BTD NM_001370658.1 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:22 O:1
• Conservation: PhyloP100: 1.63
• Publications: 14 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: ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 269 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 88 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: -0.52516 (below the threshold of 3.09). Trascript score misZ: 0.15371 (below the threshold of 3.09). GenCC associations: The gene is linked to Leigh syndrome, biotinidase deficiency.
• PP5: Variant 3-15635477-GCGGCTG-TCC is Pathogenic according to our data. Variant chr3-15635477-GCGGCTG-TCC is described in ClinVar as Pathogenic. ClinVar VariationId is 1895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370658.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTD	NM_001370658.1	MANE Select	c.38_44delGCGGCTGinsTCC	p.Cys13PhefsTer36	frameshift missense	Exon 2 of 4	NP_001357587.1	P43251-4
	BTD	NM_001281723.4		c.38_44delGCGGCTGinsTCC	p.Cys13PhefsTer36	frameshift missense	Exon 2 of 4	NP_001268652.2	P43251-4
	BTD	NM_001281724.3		c.38_44delGCGGCTGinsTCC	p.Cys13PhefsTer36	frameshift missense	Exon 4 of 6	NP_001268653.2	P43251-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTD	ENST00000643237.3	MANE Select	c.38_44delGCGGCTGinsTCC	p.Cys13PhefsTer36	frameshift missense	Exon 2 of 4	ENSP00000495254.2	P43251-4
	BTD	ENST00000303498.10	TSL:1	c.38_44delGCGGCTGinsTCC	p.Cys13PhefsTer36	frameshift missense	Exon 3 of 5	ENSP00000306477.6	P43251-4
	BTD	ENST00000427382.2	TSL:4	c.38_44delGCGGCTGinsTCC	p.Cys13PhefsTer36	frameshift missense	Exon 2 of 4	ENSP00000397113.2	P43251-4

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
18	-	-	Biotinidase deficiency (19)
4	-	-	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=2/198	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs80338684; hg19: chr3-15676984;