rs397514394

Variant names:

• chr3-15644788-G-A
• rs397514394
• NM_001370658.1:c.872G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-15644788-G-A
• chr3-15644788-G-C

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.872G>A​(p.Ser291Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.92

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, 0.985
• PP5: Variant 3-15644788-G-A is Pathogenic according to our data. Variant chr3-15644788-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3666195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644788-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTD	NM_001370658.1	c.872G>A	p.Ser291Asn	missense_variant	Exon 4 of 4	ENST00000643237.3	NP_001357587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTD	ENST00000643237.3	c.872G>A	p.Ser291Asn	missense_variant	Exon 4 of 4		NM_001370658.1	ENSP00000495254.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000454 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Biotinidase deficiency Pathogenic:2

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 311 of the BTD protein (p.Ser311Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 10400129; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Oct 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BTD c.872G>A; p.Ser291Asn variant (rs397514394), also known as c.932G>A; p.Ser311Asn for NM_000060.2, is reported in the literature in several individuals affected with biotinidase deficiency (Kannan 2022, Norrgard 1999). At least one patient carried a second pathogenic allele and exhibited substantially reduced serum biotinidase activity (Norrgard 1999). The p.Ser291Asn variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.827). Additionally, other variants at this codon (c.873T:G, p.Ser291Arg; c.872G>C, p.Ser291Thr) have been reported in individuals with biotinidase deficiency and are considered disease-causing (Carvalho 2019, Iqbal 2010, Kannan 2022). Based on available information, the p.Ser291Asn variant is considered to be likely pathogenic. References: Carvalho NO et al. Novel mutations causing biotinidase deficiency in individuals identified by the newborn screening program in Minas Gerais, Brazil. Am J Med Genet A. 2019 Jun;179(6):978-982. PMID: 30912303. Iqbal F et al. The identification of novel mutations in the biotinidase gene using denaturing high pressure liquid chromatography (dHPLC). Mol Genet Metab. 2010 May;100(1):42-5. PMID: 20083419. Kannan B et al. A Rare Biotinidase Deficiency in the Pediatrics Population: Genotype-Phenotype Analysis. J Pediatr Genet. 2022 Nov 1;12(1):1-15. PMID: 36684547. Norrgard KJ et al. Mutations causing profound biotinidase deficiency in children ascertained by newborn screening in the United States occur at different frequencies than in symptomatic children. Pediatr Res. 1999 Jul;46(1):20-7. PMID: 10400129. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;.;D;.;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	.;T;T;.;.;T;T
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	.;.;M;.;.;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.9	.;D;.;.;.;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	.;D;.;.;.;D;D
Sift4G	Uncertain	0.0050	.;D;.;.;.;D;D
Polyphen		1.0	.;.;D;.;.;.;.
Vest4		0.96, 0.98, 0.98
MutPred		0.95		.;.;Loss of glycosylation at S311 (P = 0.0016);.;.;.;.;
MVP		1.0
MPC		0.41
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.70
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: rs397514394; hg19: chr3-15686295;