3-15644461-A-T

Variant names:

• chr3-15644461-A-T
• rs397514376
• NM_001370658.1:c.545A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP5

The NM_001370658.1(BTD):​c.545A>T​(p.Asn182Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. N182S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: -0.912
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• biotinidase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, ClinGen, Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001370658.1
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 88 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: -0.52516 (below the threshold of 3.09). Trascript score misZ: 0.15371 (below the threshold of 3.09). GenCC associations: The gene is linked to Leigh syndrome, biotinidase deficiency.
• PP5: Variant 3-15644461-A-T is Pathogenic according to our data. Variant chr3-15644461-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2070102.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTD	NM_001370658.1	c.545A>T	p.Asn182Ile	missense_variant	Exon 4 of 4	ENST00000643237.3	NP_001357587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTD	ENST00000643237.3	c.545A>T	p.Asn182Ile	missense_variant	Exon 4 of 4		NM_001370658.1	ENSP00000495254.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Biotinidase deficiency Pathogenic:4 Uncertain:1

Jul 10, 2024

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 20, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 202 of the BTD protein (p.Asn202Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 20224900; internal data). 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: 2070102). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BTD protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

May 31, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM3,PM1,PM2,PP2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.0090	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	8.2
DANN	Benign	0.94
DEOGEN2	Uncertain	0.53	.;.;D;.;.;.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.88	.;D;D;.;.;D;T;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.4	.;.;L;.;.;.;.;.
PhyloP100		-0.91
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.0	.;D;.;.;.;D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0030	.;D;.;.;.;D;D;D
Sift4G	Uncertain	0.018	.;D;.;.;.;D;T;D
Polyphen		0.26	.;.;B;.;.;.;.;.
Vest4		0.69, 0.75, 0.66
MutPred		0.64		.;.;Gain of catalytic residue at N202 (P = 0.0867);.;.;.;.;.;
MVP		0.63
MPC		0.13
ClinPred		0.63	D
GERP RS		-3.8
Varity_R		0.39
gMVP		0.77
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397514376; hg19: chr3-15685968;