rs397514422

chr3-15645315-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_001370658.1(BTD):c.1399T>C(p.Trp467Arg) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.80

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001370658.1
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-15645315-T-C is Pathogenic according to our data. Variant chr3-15645315-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 25091.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-15645315-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTD	NM_001370658.1	c.1399T>C	p.Trp467Arg	missense_variant	4/4	ENST00000643237.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTD	ENST00000643237.3	c.1399T>C	p.Trp467Arg	missense_variant	4/4		NM_001370658.1	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 13, 2015

The W487R missense variant in the BTD gene has been reported previously in association with biotinidasedeficiency (Pomponio et al., 2000; ARUP BTD mutation database). Furthermore, multiple missense variantsin nearby residues (A478P, G488D, N489T, P497S) have been reported in the Human Gene MutationDatabase in association with biotinidase deficiency (Stenson et al., 2014). We consider this variant to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
Cadd	Benign	20
Dann	Benign	0.90
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.045
FATHMM_MKL	Benign	0.74	D
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.64	D;D;D;D;D;D;D
MetaSVM	Benign	-0.50	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
Polyphen		0.044	.;.;B;.;.;.;.
Vest4		0.28, 0.29, 0.27
MutPred		0.89		.;.;Gain of sheet (P = 0.0028);.;.;.;.;
MVP		0.96
MPC		0.14
ClinPred		0.38	T
GERP RS		4.4
Varity_R		0.27
gMVP		0.80

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: rs397514422; hg19: chr3-15686822;