rs80338686

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_001370658.1(BTD):c.1552C>A(p.Arg518Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,456,588 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R518C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

BTD
NM_001370658.1 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 2.06

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-15645468-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

PP5

Variant 3-15645468-C-A is Pathogenic according to our data. Variant chr3-15645468-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15645468-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTD	NM_001370658.1 linkuse as main transcript	c.1552C>A	p.Arg518Ser	missense_variant	4/4	ENST00000643237.3	NP_001357587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BTD	ENST00000643237.3 linkuse as main transcript	c.1552C>A	p.Arg518Ser	missense_variant	4/4		NM_001370658.1	ENSP00000495254	P1	P43251-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000332

AC:

AN:

240906

Hom.:

AF XY:

0.0000532

AC XY:

AN XY:

131570

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1456588

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

724720

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000413

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Biotinidase deficiency

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 08, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2023	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 538 of the BTD protein (p.Arg538Ser). This variant is present in population databases (rs80338686, gnomAD 0.03%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 22698809; Invitae). ClinVar contains an entry for this variant (Variation ID: 203642). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BTD protein function with a positive predictive value of 95%. This variant disrupts the p.Arg538 amino acid residue in BTD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9099842, 26810761, 27207447). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Arcensus	Feb 01, 2013	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.48

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

.;.;D;.;.;.;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.91

.;D;D;.;.;D;D

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.2

.;.;M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-5.8

.;D;.;.;.;D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

.;D;.;.;.;D;D

Sift4G

Uncertain

0.0030

.;D;.;.;.;D;D

Polyphen

1.0

.;.;D;.;.;.;.

Vest4

0.97, 0.97

MutPred

0.82

.;.;Loss of sheet (P = 0.0315);.;.;.;.;

MVP

0.93

MPC

0.45

ClinPred

0.97

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over