rs397514366

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001370658.1(BTD):ā€‹c.455A>Gā€‹(p.Asn152Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,008 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 (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 31)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

BTD
NM_001370658.1 missense

Scores

7
10
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 9.32
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BTDNM_001370658.1 linkuse as main transcriptc.455A>G p.Asn152Ser missense_variant 4/4 ENST00000643237.3 NP_001357587.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BTDENST00000643237.3 linkuse as main transcriptc.455A>G p.Asn152Ser missense_variant 4/4 NM_001370658.1 ENSP00000495254 P1P43251-4

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152122
Hom.:
0
Cov.:
31
show subpopulations
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251344
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135832
show subpopulations
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461886
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727242
show subpopulations
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152122
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74300
show subpopulations
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Biotinidase deficiency Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 15, 2022This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 172 of the BTD protein (p.Asn172Ser). This variant is present in population databases (rs397514366, gnomAD 0.0009%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 11313766). ClinVar contains an entry for this variant (Variation ID: 25017). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -
Uncertain significance, criteria provided, single submitterclinical testingCounsylNov 09, 2017- -
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Jan 29, 2021- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 23, 2022The c.515A>G (p.N172S) alteration is located in exon 4 (coding exon 4) of the BTD gene. This alteration results from a A to G substitution at nucleotide position 515, causing the asparagine (N) at amino acid position 172 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
-0.040
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.58
.;.;D;.;.;.;T;.
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.88
.;D;D;.;.;D;D;D
M_CAP
Uncertain
0.092
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.77
D
MutationAssessor
Pathogenic
3.3
.;.;M;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.53
T
PROVEAN
Pathogenic
-4.8
.;D;.;.;.;D;D;D
REVEL
Pathogenic
0.78
Sift
Uncertain
0.0030
.;D;.;.;.;D;D;D
Sift4G
Uncertain
0.0050
.;D;.;.;.;D;D;D
Polyphen
1.0
.;.;D;.;.;.;.;.
Vest4
0.92, 0.92, 0.91
MutPred
0.93
.;.;Gain of disorder (P = 0.0647);.;.;.;.;.;
MVP
0.99
MPC
0.38
ClinPred
0.99
D
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.77
gMVP
0.95

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397514366; hg19: chr3-15685878; API