3-15645140-C-T

Position:

• chr3-15645140-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2_Supporting

The NM_001370658.1(BTD):​c.1224C>T​(p.Tyr408Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,614,132 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (50 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (30 hom.)
• Consequence: BTD NM_001370658.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0410

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-15645140-C-T is Benign according to our data. Variant chr3-15645140-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 38593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15645140-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.041 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0109 (1667/152250) while in subpopulation AFR AF= 0.038 (1579/41546). AF 95% confidence interval is 0.0364. There are 50 homozygotes in gnomad4. There are 786 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 50 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTD	NM_001370658.1	c.1224C>T	p.Tyr408Tyr	synonymous_variant	4/4	ENST00000643237.3	NP_001357587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BTD	ENST00000643237.3	c.1224C>T	p.Tyr408Tyr	synonymous_variant	4/4		NM_001370658.1	ENSP00000495254.2

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1647 AN: 152132 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.0376

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00308 AC: 775 AN: 251380 Hom.: 11 AF XY: 0.00221 AC XY: 300 AN XY: 135852

Gnomad AFR exome AF: 0.0383

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00126 AC: 1841 AN: 1461882 Hom.: 30 Cov.: 31 AF XY: 0.00113 AC XY: 823 AN XY: 727242

Gnomad4 AFR exome AF: 0.0399

Gnomad4 AMR exome AF: 0.00360

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000122

Gnomad4 OTH exome AF: 0.00258

GnomAD4 genome AF: 0.0109 AC: 1667 AN: 152250 Hom.: 50 Cov.: 32 AF XY: 0.0106 AC XY: 786 AN XY: 74446

Gnomad4 AFR AF: 0.0380

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00625 Hom.: 5

Bravo AF: 0.0126

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 16, 2021	The p.Tyr428Tyr variant in BTD is classified as likely benign because it does not alter an amino acid residue, is not located within the splice consensus site, and computational splice prediction tools do not predict an impact on splicing. It has been identified in 3.8% (942/24956) of African chromosomes, including 15 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BS1, BP4, BP7. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 19, 2013	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 30, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2019	This variant is associated with the following publications: (PMID: 15776412, 26361991, 28498829, 25174816, 25967232, 20224900, 19757147) -

Biotinidase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Sep 17, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.55
DANN	Benign	0.18

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

Publications

LitVar

Other links and lift over

dbSNP: rs35145938; hg19: chr3-15686647;