rs397514337

chr3-15635538-C-Achr3-15635538-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001370658.1(BTD):c.99C>A(p.His33Gln) 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 benign outcome for this variant. Variant has been reported in Lovd as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. H33H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.875

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-15635538-C-A is Pathogenic according to our data. Variant chr3-15635538-C-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.37256885).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTD	NM_001370658.1	c.99C>A	p.His33Gln	missense_variant	2/4	ENST00000643237.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTD	ENST00000643237.3	c.99C>A	p.His33Gln	missense_variant	2/4		NM_001370658.1	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	0.083
Dann	Benign	0.69
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.20	N
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.20	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-5.6	D;N;.;.;.;.;N;N;N;.
REVEL	Uncertain	0.51
Sift	Benign	0.14	T;T;.;.;.;.;T;T;T;.
Sift4G	Benign	0.57	T;T;.;.;.;.;T;T;T;.
Polyphen		0.0030	.;.;B;.;.;.;.;.;.;.
Vest4		0.59, 0.69, 0.54
MutPred		0.71		.;.;Gain of sheet (P = 0.0061);.;Gain of sheet (P = 0.0061);.;.;.;.;.;
MVP		0.74
MPC		0.072
ClinPred		0.10	T
GERP RS		-3.2
Varity_R		0.025
gMVP		0.34

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: rs397514337; hg19: chr3-15677045;