rs397514369

Positions:

• chr3-15644413-G-A

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.497G>A​(p.Cys166Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,890 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 0.000010 (1 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.98

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, 0.991
• PP5: Variant 3-15644413-G-A is Pathogenic according to our data. Variant chr3-15644413-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 25020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644413-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTD	NM_001370658.1	c.497G>A	p.Cys166Tyr	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.497G>A	p.Cys166Tyr	missense_variant	4/4		NM_001370658.1	ENSP00000495254.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251430 Hom.: 1 AF XY: 0.0000294 AC XY: 4 AN XY: 135874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461890 Hom.: 1 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727244

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: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Alfa AF: 0.00152 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Biotinidase deficiency Pathogenic:8

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 186 of the BTD protein (p.Cys186Tyr). This variant is present in population databases (rs397514369, gnomAD 0.02%). This missense change has been observed in individual(s) with profound or partial biotinidase deficiency, and suspected BTD deficiency (PMID: 10801053, 22011816, 23644139, 25754625). ClinVar contains an entry for this variant (Variation ID: 25020). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 06, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jul 11, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Likely pathogenic, criteria provided, single submitter	research	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 04, 2024	PM3 (strong),PM2,PP3,PM1,PM5 -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 23, 2023	Variant summary: BTD c.497G>A (p.Cys166Tyr) 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 allele was found at a frequency of 2e-05 in 251430 control chromosomes in the gnomAD database, including 1 homozygote. c.497G>A has been reported in the literature in multiple individuals affected with Biotinidase Deficiency, including a homozygous individual with profound biotinidase deficiency and compound heterozygous cases with other (likely) pathogenic variants (Ben-Rebeh_2012, Ercan_2020, Kasapkara_2015, Pomponio_2000, Thodi_2013). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 10801053, 33189081, 22011816, 23644139, 22106832, 25423671). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2022	The p.Cys186Tyr variant in BTD has been reported in at least 4 compound heterozygous individuals with partial Biotinidase deficiency and reduced Biotinidase activity in their serum (Pomponio 2000 PubMed: 10801053; Ben-Rebeh 2012 PMID: 22106832; Thodi 2013 PMID: 23644139; Al Hosani 2014 PMID: 24932929) and in 15 newborns with Biotinidase deficiency (Karaca 2015 PMID: 25754625; Seker Yilmaz 2018 PMID: 29353266). It was also observed in ClinVar (Variation ID 25020) but absent in gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant disrupts a functional cysteine that is likely important for protein function (Karaca 2015 PMID: 25754625). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive partial Biotinidase deficiency. ACMG/AMP Criteria applied: PM3_VeryStrong, PM1_Supporting, PM2_Supporting, PP3, PP4. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 11, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	.;.;D;.;.;.;D;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	.;D;D;.;.;D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	.;.;M;.;.;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-10	.;D;.;.;.;D;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	.;D;.;.;.;D;D;D
Sift4G	Pathogenic	0.0	.;D;.;.;.;D;D;D
Polyphen		1.0	.;.;D;.;.;.;.;.
Vest4		0.95, 0.97, 0.95
MutPred		0.91		.;.;Loss of methylation at K188 (P = 0.0714);.;.;.;.;.;
MVP		1.0
MPC		0.54
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.99

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: rs397514369; hg19: chr3-15685920;