rs745343884

Positions:

• chr3-15644335-G-A
• chr3-15644335-G-C
• chr3-15644335-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001370658.1(BTD):​c.419G>A​(p.Cys140Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,810 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 10.0

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 3-15644335-G-A is Pathogenic according to our data. Variant chr3-15644335-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2203313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTD	NM_001370658.1	c.419G>A	p.Cys140Tyr	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.419G>A	p.Cys140Tyr	missense_variant	4/4		NM_001370658.1	ENSP00000495254	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461810 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727206

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Biotinidase deficiency Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 10, 2023	ClinVar contains an entry for this variant (Variation ID: 2203313). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 25174816). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 160 of the BTD protein (p.Cys160Tyr). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys160 amino acid residue in BTD. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects BTD function (PMID: 31337602). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 16, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 21, 2024	Variant summary: BTD c.419G>A (p.Cys140Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251084 control chromosomes. c.419G>A has been reported in the literature in at-least one individual affected with Biotinidase Deficiency (Borsatto_2014). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence that variant reduced normal activity (Borsatto_2019). The following publications have been ascertained in the context of this evaluation (PMID: 25174816, 31337602).ClinVar contains an entry for this variant (Variation ID: 2203313). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	.;.;D;.;.;.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	.;D;D;.;.;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.8	.;.;H;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-11	.;D;.;.;.;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	.;D;.;.;.;D;D;D
Sift4G	Uncertain	0.0020	.;D;.;.;.;D;D;D
Polyphen		1.0	.;.;D;.;.;.;.;.
Vest4		0.98, 0.98, 0.98
MutPred		0.72		.;.;Gain of phosphorylation at C160 (P = 0.0647);.;.;.;.;.;
MVP		0.99
MPC		0.54
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.98

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: rs745343884; hg19: chr3-15685842;