rs104893686

Positions:

• chr3-15645063-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001370658.1(BTD):​c.1147T>G​(p.Phe383Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 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 Conflicting classifications of pathogenicity,other (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications P:4 U:1 O:1
• Conservation: PhyloP100: 7.96

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 3-15645063-T-G is Pathogenic according to our data. Variant chr3-15645063-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity, other]. Clinvar id is 143949.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, other=1, Uncertain_significance=1, Pathogenic=2}. Variant chr3-15645063-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTD	NM_001370658.1	c.1147T>G	p.Phe383Val	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.1147T>G	p.Phe383Val	missense_variant	4/4		NM_001370658.1	ENSP00000495254	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251384 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135860

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

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: 0.00000274 AC: 4 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: 0.0000894

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.: 32

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity; other

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Biotinidase deficiency Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 29, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 12, 2023	Variant summary: BTD c.1147T>G (p.Phe383Val), also known as c.1207T>G (p.Phe403Val), results in a non-conservative amino acid change located in the vanin, C-terminal domain (IPR043957) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251384 control chromosomes (gnomAD). c.1147T>G has been reported in the literature, frequently observed in cis with c.1270G>C (p.Asp424His, also known as p.Asp444His), in multiple individuals affected with Biotinidase Deficiency, including several cases where the variant was observed in the homozygous state in cis with p.Asp424His in patients with profound Biotinidase Deficiency (e.g. Norrgard_1999, Hesermann_2012, Al Hosani_2014, Haines_2014, Jay_2015, Al-Jasmi_2016, Khan_2021, Saleh_2021). p.Asp424His is known to be associated with partial Biotinidase deficiency when in compound heterozygosity with other BTD variants associated with a mild or a severe phenotype, while homozygous individuals are expected to be unaffected (as described in ClinVar submission by our laboratory, SCV001363363.2). Given p.Asp424His is linked to partial Biotinidase deficiency, and provided that homozygous patients with [F383V;D424H] showed profound biotinidase deficiency, the variant of interest is implied to have an adverse effect on enzyme function. These data indicate that the variant is likely to be associated with disease. Of interest is a recent report by Hou et al (2020), describing the variant in a compound heterozygosity with p.Asp424His in an individual with no associated disease phenotype. The following publications have been ascertained in the context of this evaluation (PMID: 26589311, 24516753, 24932929, 22698809, 24525934, 31980526, 25144890, 34166817, 10400129, 34374989). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Two classified the variant as pathogenic/likely pathogenic, and one classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 14, 2021	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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 143949). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 10400129, 22698809, 24525934, 26589311). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with valine at codon 403 of the BTD protein (p.Phe403Val). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and valine. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant is also known as c.1270G>C (p.Phe397Val) when using an alternative transcript (NM_001370658.1). The c.1207T>G (p.Phe403Val) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0016% (4/251384) and is absent in the homozygous state, thus is presumed to be rare. The c.1207T>G (p.Phe403Val) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has been previously reported as complex allele in conjunction with the p.Asp444His (c.[1207T>G;1330G>C] (p.[Phe403Val;Asp444His]) also known as c.[1147T>G;1270G>C] (p.[Phe383Val;Asp424His])) in patients with biotinidase deficiency and partial biotinidase deficiency (PMID: 10400129, 24525934, 25144890). Functional studies showed that the p.Asp444His variant in conjunction with the p.Phe403Val variant leads to absent biotinidase levels (PMID: 10400129). Based on the available evidence, the c.[1207T>G;1330G>C] complex allele is classified as Pathogenic. -

not provided Pathogenic:1 Other:1

other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 02, 2018	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 26, 2023	The frequency of this variant in the general population, 0.00012 (4/34590 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has only been reported as a complex allele associated with profound biotinidase deficiency in homozygous individuals or those with another profound deficiency allele affected with paraparesis, optic neuropathy, and speech delay (PMIDs: 22698809 (2012), 24525934 (2014), 24932929 (2014), 26589311 (2015), 33016994 (2020), 34374989 (2021)). The complex allele with just c.1330G>C (p.Asp444His) on the other allele resulted in partial biotinidase deficiency (PMID: 25144890 (2015)).Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	.;.;D;.;.;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;D;D;.;.;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.4	.;.;M;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.6	.;D;.;.;.;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	.;D;.;.;.;D;D
Sift4G	Uncertain	0.0020	.;D;.;.;.;D;D
Polyphen		1.0	.;.;D;.;.;.;.
Vest4		0.87, 0.87, 0.87
MutPred		0.95		.;.;Gain of phosphorylation at Y400 (P = 0.0936);.;.;.;.;
MVP		0.99
MPC		0.47
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.88
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: rs104893686; hg19: chr3-15686570;