rs750363004

Positions:

• chr3-15644438-C-G
• chr3-15644438-C-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.522C>G​(p.Phe174Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,894 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: 0.0000014 (0 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 0.0500

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, 0.949
• PP5: Variant 3-15644438-C-G is Pathogenic according to our data. Variant chr3-15644438-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 587716.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.522C>G	p.Phe174Leu	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.522C>G	p.Phe174Leu	missense_variant	4/4		NM_001370658.1	ENSP00000495254	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251448 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Biotinidase deficiency Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 16, 2023	ClinVar contains an entry for this variant (Variation ID: 587716). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 26810761; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 194 of the BTD protein (p.Phe194Leu). 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. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 11, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	.;.;D;.;.;.;T;.
Eigen	Benign	0.035
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	.;T;T;.;.;T;D;T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.1	.;.;M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.8	.;D;.;.;.;D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0050	.;D;.;.;.;D;D;D
Sift4G	Uncertain	0.0090	.;D;.;.;.;D;D;D
Polyphen		1.0	.;.;D;.;.;.;.;.
Vest4		0.90, 0.92, 0.89
MutPred		0.83		.;.;Gain of disorder (P = 0.1786);.;.;.;.;.;
MVP		0.91
MPC		0.43
ClinPred		0.98	D
GERP RS		-1.3
Varity_R		0.86
gMVP		0.92

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: rs750363004; hg19: chr3-15685945;