3-15645190-G-T

Position:

chr3-15645190-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_001370658.1(BTD):c.1274G>T(p.Gly425Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,614,048 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. G425E) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

BTD
NM_001370658.1 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 4.22

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 18 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001370658.1

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-15645190-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 556288.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 3-15645190-G-T is Pathogenic according to our data. Variant chr3-15645190-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 25082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15645190-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTD	NM_001370658.1 linkuse as main transcript	c.1274G>T	p.Gly425Val	missense_variant	4/4	ENST00000643237.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTD	ENST00000643237.3 linkuse as main transcript	c.1274G>T	p.Gly425Val	missense_variant	4/4		NM_001370658.1	P1	P43251-4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727242

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000322

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Biotinidase deficiency

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 25, 2023	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 445 of the BTD protein (p.Gly445Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with both profound and partial biotinidase deficiency (PMID: 9396567, 15776412). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 25082). 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. This variant disrupts the p.Gly445 amino acid residue in BTD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20224900). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 22, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 19, 2021	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

May 03, 2019

Not found in the total gnomAD dataset, and the data is high quality (0/282830 chr). Found in at least two symptomatic patients. Predicted to have a damaging effect on the protein. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

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

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

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

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

3.2

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

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-8.1

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

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.92, 0.93, 0.91

MutPred

0.97

.;.;Gain of sheet (P = 0.0344);.;.;.;.;

MVP

0.99

MPC

0.46

ClinPred

1.0

GERP RS

4.7

Varity_R

0.87

gMVP

0.96

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