rs774018881

Positions:

• chr3-15645372-C-A
• chr3-15645372-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001370658.1(BTD):​c.1456C>A​(p.Leu486Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.44

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTD	NM_001370658.1	c.1456C>A	p.Leu486Ile	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	c.1456C>A	p.Leu486Ile	missense_variant	4/4		NM_001370658.1	ENSP00000495254	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Biotinidase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 09, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with BTD-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with isoleucine at codon 506 of the BTD protein (p.Leu506Ile). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	.;.;D;.;.;.;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.021
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.80	.;T;T;.;.;T;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.8	.;.;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.6	.;N;.;N;.;N;N
REVEL	Uncertain	0.61
Sift	Uncertain	0.024	.;D;.;T;.;D;D
Sift4G	Uncertain	0.0090	.;D;.;.;.;D;D
Polyphen		1.0	.;.;D;.;.;.;.
Vest4		0.51, 0.49, 0.48
MutPred		0.78		.;.;Gain of loop (P = 0.069);.;.;.;.;
MVP		0.97
MPC		0.39
ClinPred		0.90	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.66

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: rs774018881; hg19: chr3-15686879;