rs104893688

Variant names:

• chr3-15645451-C-T
• rs104893688
• NM_001370658.1:c.1535C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PP2 PP3_Moderate PP5_Very_Strong

The NM_001370658.1(BTD):​c.1535C>T​(p.Thr512Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,611,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T512T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23
• Conservation: PhyloP100: 7.34
• Publications: 30 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 13 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_001370658.1
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.857
• PP5: Variant 3-15645451-C-T is Pathogenic according to our data. Variant chr3-15645451-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1897.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.1535C>T	p.Thr512Met	missense	Exon 4 of 4	NP_001357587.1	P43251-4
	BTD	NM_001281723.4		c.1535C>T	p.Thr512Met	missense	Exon 4 of 4	NP_001268652.2	P43251-4
	BTD	NM_001281724.3		c.1535C>T	p.Thr512Met	missense	Exon 6 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.1535C>T	p.Thr512Met	missense	Exon 4 of 4	ENSP00000495254.2	P43251-4
	BTD	ENST00000303498.10	TSL:1	c.1535C>T	p.Thr512Met	missense	Exon 5 of 5	ENSP00000306477.6	P43251-4
	BTD	ENST00000427382.2	TSL:4	c.1535C>T	p.Thr512Met	missense	Exon 4 of 4	ENSP00000397113.2	P43251-4

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000693 AC: 17 AN: 245398 AF XY: 0.0000825

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000127

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000117 AC: 171 AN: 1459576 Hom.: 0 Cov.: 31 AF XY: 0.000113 AC XY: 82 AN XY: 726104

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86256

European-Finnish (FIN) AF: 0.0000782 AC: 4 AN: 51150

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000127 AC: 141 AN: 1111986

Other (OTH) AF: 0.000232 AC: 14 AN: 60382

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74462

African (AFR) AF: 0.0000241 AC: 1 AN: 41554

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000954 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000495 AC: 6

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
15	-	-	Biotinidase deficiency (15)
6	-	-	not provided (6)
1	-	-	BTD-related disorder (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.025	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MVP		0.93
MPC		0.43
ClinPred		0.90	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.95
Mutation Taster		=4/96	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: rs104893688; hg19: chr3-15686958; COSMIC: COSV100329741; COSMIC: COSV100329741;