rs35034250

chr3-15645027-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001370658.1(BTD):c.1111C>T(p.Pro371Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,614,166 control chromosomes in the GnomAD database, including 431 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P371L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (30 hom., cov: 32)
  • Exomes 𝑓: 0.022 (401 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.172

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031863153).
• BP6: Variant 3-15645027-C-T is Benign according to our data. Variant chr3-15645027-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 38570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15645027-C-T is described in Lovd as [Pathogenic]. Variant chr3-15645027-C-T is described in Lovd as [Benign]. Variant chr3-15645027-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.015 (2289/152286) while in subpopulation NFE AF= 0.0251 (1709/68018). AF 95% confidence interval is 0.0241. There are 30 homozygotes in gnomad4. There are 1039 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTD	NM_001370658.1	c.1111C>T	p.Pro371Ser	missense_variant	4/4	ENST00000643237.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTD	ENST00000643237.3	c.1111C>T	p.Pro371Ser	missense_variant	4/4		NM_001370658.1	P1

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2287 AN: 152168 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.00499

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0251

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.0139 AC: 3500 AN: 251428 Hom.: 47 AF XY: 0.0140 AC XY: 1903 AN XY: 135876

Gnomad AFR exome AF: 0.00474

Gnomad AMR exome AF: 0.00546

Gnomad ASJ exome AF: 0.00456

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00532

Gnomad FIN exome AF: 0.0108

Gnomad NFE exome AF: 0.0238

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.0219 AC: 32039 AN: 1461880 Hom.: 401 Cov.: 31 AF XY: 0.0211 AC XY: 15346 AN XY: 727240

Gnomad4 AFR exome AF: 0.00391

Gnomad4 AMR exome AF: 0.00635

Gnomad4 ASJ exome AF: 0.00436

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00511

Gnomad4 FIN exome AF: 0.0112

Gnomad4 NFE exome AF: 0.0263

Gnomad4 OTH exome AF: 0.0202

GnomAD4 genome AF: 0.0150 AC: 2289 AN: 152286 Hom.: 30 Cov.: 32 AF XY: 0.0140 AC XY: 1039 AN XY: 74456

Gnomad4 AFR AF: 0.00498

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00643

Gnomad4 FIN AF: 0.0118

Gnomad4 NFE AF: 0.0251

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.0216 Hom.: 73

Bravo AF: 0.0147

TwinsUK AF: 0.0237 AC: 88

ALSPAC AF: 0.0280 AC: 108

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0241 AC: 207

ExAC AF: 0.0140 AC: 1698

EpiCase AF: 0.0239

EpiControl AF: 0.0204

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 26, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 22, 2017	- -

Biotinidase deficiency Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 04, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	BTD: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 12, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	6.7
Dann	Benign	0.43
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.24	N
MetaRNN	Benign	0.0032	T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.25	T
Polyphen		0.0020	.;.;B;.;.;.;.
Vest4		0.064, 0.031, 0.041
MPC		0.072
ClinPred		0.0015	T
GERP RS		2.2
Varity_R		0.023
gMVP		0.50

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: rs35034250; hg19: chr3-15686534;