rs139829181

chr3-15644422-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001370658.1(BTD):c.506A>G(p.Asp169Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,892 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.31

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 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001370658.1
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTD	NM_001370658.1	c.506A>G	p.Asp169Gly	missense_variant	4/4	ENST00000643237.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTD	ENST00000643237.3	c.506A>G	p.Asp169Gly	missense_variant	4/4		NM_001370658.1	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251440 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135882

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

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: 0.00000205 AC: 3 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000166

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Biotinidase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 189 of the BTD protein (p.Asp189Gly). This variant is present in population databases (rs139829181, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of biotinidase deficiency (PMID: 26810761). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.55	T
Polyphen		1.0	.;.;D;.;.;.;.;.
Vest4		0.86, 0.86, 0.85
MVP		0.99
MPC		0.48
ClinPred		0.98	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.87
gMVP		0.94

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: rs139829181; hg19: chr3-15685929;