rs145388314

Variant names:

• chr3-15644501-C-T
• rs145388314
• NM_001370658.1:c.585C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6 BP7 BS2_Supporting

The NM_001281723.4(BTD):​c.585C>T​(p.Leu195Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00869 in 1,614,172 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0066 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0089 (68 hom.)
• Consequence: BTD NM_001281723.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -0.899
• Publications: 5 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 3-15644501-C-T is Benign according to our data. Variant chr3-15644501-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 25032.
• BP7: Synonymous conserved (PhyloP=-0.899 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 6 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001281723.4. 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.585C>T	p.Leu195Leu	synonymous	Exon 4 of 4	NP_001357587.1
	BTD	NM_001281723.4		c.585C>T	p.Leu195Leu	synonymous	Exon 4 of 4	NP_001268652.2
	BTD	NM_001281724.3		c.585C>T	p.Leu195Leu	synonymous	Exon 6 of 6	NP_001268653.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTD	ENST00000643237.3	MANE Select	c.585C>T	p.Leu195Leu	synonymous	Exon 4 of 4	ENSP00000495254.2
	BTD	ENST00000303498.10	TSL:1	c.585C>T	p.Leu195Leu	synonymous	Exon 5 of 5	ENSP00000306477.6
	BTD	ENST00000427382.2	TSL:4	c.585C>T	p.Leu195Leu	synonymous	Exon 4 of 4	ENSP00000397113.2

Frequencies

GnomAD3 genomes AF: 0.00661 AC: 1006 AN: 152162 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00413

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00735

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00997

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00798 AC: 2006 AN: 251478 AF XY: 0.00797

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00358

Gnomad ASJ exome AF: 0.0332

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00841

Gnomad NFE exome AF: 0.0111

Gnomad OTH exome AF: 0.00928

GnomAD4 exome AF: 0.00891 AC: 13021 AN: 1461892 Hom.: 68 Cov.: 31 AF XY: 0.00874 AC XY: 6354 AN XY: 727248

African (AFR) AF: 0.00140 AC: 47 AN: 33478

American (AMR) AF: 0.00371 AC: 166 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0335 AC: 876 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00128 AC: 110 AN: 86258

European-Finnish (FIN) AF: 0.00754 AC: 403 AN: 53420

Middle Eastern (MID) AF: 0.00711 AC: 41 AN: 5768

European-Non Finnish (NFE) AF: 0.00976 AC: 10848 AN: 1112012

Other (OTH) AF: 0.00876 AC: 529 AN: 60396

GnomAD4 genome AF: 0.00661 AC: 1006 AN: 152280 Hom.: 6 Cov.: 31 AF XY: 0.00616 AC XY: 459 AN XY: 74472

African (AFR) AF: 0.00123 AC: 51 AN: 41568

American (AMR) AF: 0.00412 AC: 63 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0317 AC: 110 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.00735 AC: 78 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00997 AC: 678 AN: 68012

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00976 Hom.: 7

Bravo AF: 0.00676

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0131

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Biotinidase deficiency (4)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	2.1
DANN	Benign	0.73
PhyloP100		-0.90
Mutation Taster		=100/0	polymorphism

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: rs145388314; hg19: chr3-15686008;