NM_001370658.1:c.1145A>G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001370658.1(BTD):c.1145A>G(p.Asn382Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000339 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

BTD
NM_001370658.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 4.88

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]

BTD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.40560225).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTD	NM_001370658.1 link	c.1145A>G	p.Asn382Ser	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 link	c.1145A>G	p.Asn382Ser	missense_variant	Exon 4 of 4		NM_001370658.1	ENSP00000495254.2		P43251-4

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000167

AC:

AN:

251392

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000334

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000354

AC:

518

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000327

AC XY:

238

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000337

Gnomad4 NFE exome

AF:

0.000436

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000191

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000385

Hom.:

Bravo

AF:

0.000144

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Biotinidase deficiency

Uncertain:4

Jul 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 402 of the BTD protein (p.Asn402Ser). This variant is present in population databases (rs201023772, gnomAD 0.03%). This missense change has been observed in individual(s) with partial biotinidase deficiency (PMID: 20224900, 25144890). ClinVar contains an entry for this variant (Variation ID: 25062). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Nov 08, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 11, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Uncertain:1

Aug 01, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BTD c.1145A>G (p.Asn382Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 251392 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BTD causing Biotinidase Deficiency (0.00017 vs 0.0046), allowing no conclusion about variant significance. c.1145A>G has been reported in the literature as a compound heterozygous genotype with partial biotinidase deficiency or a presumably compound heterozygous genotype in settings of newborn screening workup among individuals affected with Partial Biotinidase Deficiency (e.g. Ohlsson_2010, Jay_2015, Sharma_2024). These report(s) do not provide unequivocal conclusions about association of the variant with Biotinidase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25144890, 20224900, 38299772). ClinVar contains an entry for this variant (Variation ID: 25062). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Oct 12, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

.;.;T;.;.;.;.

Eigen

Benign

0.17

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

.;D;D;.;.;D;D

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.41

T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Uncertain

2.8

.;.;M;.;.;.;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.4

.;N;.;.;.;N;N

REVEL

Uncertain

0.46

Sift

Benign

0.59

.;T;.;.;.;T;T

Sift4G

Benign

0.67

.;T;.;.;.;T;T

Polyphen

0.85

.;.;P;.;.;.;.

Vest4

0.72, 0.78, 0.71

MVP

0.97

MPC

0.18

ClinPred

0.14

GERP RS

3.0

Varity_R

0.061

gMVP

0.57

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over