rs397514357

chr3-15642022-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_001370658.1(BTD):c.364C>A(p.Pro122Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,878 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P122S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 7.91

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr3-15642022-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2833416.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 3-15642022-C-A is Pathogenic according to our data. Variant chr3-15642022-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 25004.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=2}. Variant chr3-15642022-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTD	NM_001370658.1	c.364C>A	p.Pro122Thr	missense_variant	3/4	ENST00000643237.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTD	ENST00000643237.3	c.364C>A	p.Pro122Thr	missense_variant	3/4		NM_001370658.1	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Biotinidase deficiency Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 30, 2023	This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 19757147, 26361991, 26589311). ClinVar contains an entry for this variant (Variation ID: 25004). 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. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 142 of the BTD protein (p.Pro142Thr). -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Dec 28, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Jul 15, 2019	- -

BTD-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 02, 2023

The BTD c.424C>A variant is predicted to result in the amino acid substitution p.Pro142Thr. This variant is absent from a large population database (gnomad.broadinstitute.org), indicating it is rare. Furthermore, it has been reported in the homozygous or compound heterozygous state in several patients with profound biotinidase deficiency (Sarafoglou et al. 2009. PubMed ID: 19757147; Al-Jasmi et al. 2016. PubMed ID: 26589311; Gannavarapu et al. 2015. PubMed ID: 26361991; Tangeraas et al. 2020. PubMedID: 33123633). Taken together, we interpret this variant as pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2016

The P142T pathogenic variant in the BTD gene has been reported previously in the compound heterozygous and homozygous states in individuals with biotinidase deficiency (Sarafoglou et al., 2009; Gannavarapu et al., 2015). The P142T variant is not observed in large population cohorts (Lek et al., 2016; Exome Variant Server). The P142T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The P142T variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2019

The alteration results in an amino acid change:_x000D_ _x000D_ The c.424C>A (p.P142T) alteration is located in coding exon 3 of the BTD gene. This alteration results from a C to A substitution at nucleotide position 424, causing the proline (P) at amino acid position 142 to be replaced by a threonine (T). The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the BTD c.424C>A alteration was not observed with coverage at this location. The amino acid change has been observed in affected individuals: _x000D_ _x000D_ The p.P142T alteration has been reported heterozygous with a second alteration in the BTD gene and homozygous in patients with profound biotinidase deficiency. The majority of reported patients with this alteration to date are of Somali heritage (Sarafoglou, 2009; Gannavarapu, 2015). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.P142 amino acid is conserved in available vertebrate species. The alteration is predicted deleterious by in silico models:_x000D_ _x000D_ The p.P142T alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.50	T
Polyphen		1.0	.;.;D;.;.;.;.;.;.;.
Vest4		0.94, 0.94
MutPred		0.84		.;.;Loss of catalytic residue at P142 (P = 0.1174);.;Loss of catalytic residue at P142 (P = 0.1174);.;.;.;.;.;
MVP		0.98
MPC		0.44
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.93

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: rs397514357; hg19: chr3-15683529;