rs147057169

Variant names:

• chr3-15635640-C-T
• rs147057169
• NM_001370658.1:c.201C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6 BP7 BS2_Supporting

The NM_001370658.1(BTD):​c.201C>T​(p.Asn67Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,614,200 control chromosomes in the GnomAD database, including 11 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 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (11 hom.)
• Consequence: BTD NM_001370658.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.422
• Publications: 3 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 3-15635640-C-T is Benign according to our data. Variant chr3-15635640-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 290069.
• BP7: Synonymous conserved (PhyloP=0.422 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 11 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_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.201C>T	p.Asn67Asn	synonymous	Exon 2 of 4	NP_001357587.1	P43251-4
	BTD	NM_001281723.4		c.201C>T	p.Asn67Asn	synonymous	Exon 2 of 4	NP_001268652.2	P43251-4
	BTD	NM_001281724.3		c.201C>T	p.Asn67Asn	synonymous	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.201C>T	p.Asn67Asn	synonymous	Exon 2 of 4	ENSP00000495254.2	P43251-4
	BTD	ENST00000303498.10	TSL:1	c.201C>T	p.Asn67Asn	synonymous	Exon 3 of 5	ENSP00000306477.6	P43251-4
	BTD	ENST00000427382.2	TSL:4	c.201C>T	p.Asn67Asn	synonymous	Exon 2 of 4	ENSP00000397113.2	P43251-4

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 234 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00247

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00162 AC: 407 AN: 251392 AF XY: 0.00172

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00208 AC: 3047 AN: 1461894 Hom.: 11 Cov.: 32 AF XY: 0.00204 AC XY: 1480 AN XY: 727248

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.00123 AC: 55 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000497 AC: 13 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000927 AC: 80 AN: 86258

European-Finnish (FIN) AF: 0.00165 AC: 88 AN: 53420

Middle Eastern (MID) AF: 0.00589 AC: 34 AN: 5768

European-Non Finnish (NFE) AF: 0.00235 AC: 2615 AN: 1112012

Other (OTH) AF: 0.00250 AC: 151 AN: 60396

GnomAD4 genome AF: 0.00154 AC: 234 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.00153 AC XY: 114 AN XY: 74482

African (AFR) AF: 0.000385 AC: 16 AN: 41570

American (AMR) AF: 0.00222 AC: 34 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00247 AC: 168 AN: 68020

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00220 Hom.: 2

Bravo AF: 0.00174

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.1
DANN	Benign	0.83
PhyloP100		0.42
PromoterAI		-0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147057169; hg19: chr3-15677147;