rs397514427

Positions:

• chr3-15645387-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001370658.1(BTD):​c.1471C>G​(p.Gln491Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: BTD NM_001370658.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 3.01

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-15645387-C-G is Pathogenic according to our data. Variant chr3-15645387-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 25097.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}. Variant chr3-15645387-C-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.24839345). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTD	NM_001370658.1	c.1471C>G	p.Gln491Glu	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.1471C>G	p.Gln491Glu	missense_variant	4/4		NM_001370658.1	ENSP00000495254.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251214 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135774

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

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: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461838 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727220

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: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74340

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Biotinidase deficiency Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 15, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 11, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	20
DANN	Benign	0.81
DEOGEN2	Benign	0.23	.;.;T;.;.;.;.
Eigen	Benign	-0.20
Eigen_PC	Benign	0.014
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.74	.;T;T;.;.;T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.89	.;.;L;.;.;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.21	.;N;.;.;.;N;N
REVEL	Uncertain	0.46
Sift	Benign	1.0	.;T;.;.;.;T;T
Sift4G	Benign	0.93	.;T;.;.;.;T;T
Polyphen		0.20	.;.;B;.;.;.;.
Vest4		0.61, 0.70, 0.48
MVP		0.95
MPC		0.098
ClinPred		0.073	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.70

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: rs397514427; hg19: chr3-15686894;