rs397507176

Positions:

chr3-15644824-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP5BP4BS1_SupportingBS2_Supporting

The NM_001370658.1(BTD):c.908A>G(p.His303Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000952 in 1,614,216 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 24 hom. )

Consequence

BTD
NM_001370658.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:7

Conservation

PhyloP100: 7.25

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 Likely_benign. Variant got -2 ACMG points.

PP5

Variant 3-15644824-A-G is Pathogenic according to our data. Variant chr3-15644824-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38278.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=6, Pathogenic=3, Likely_pathogenic=3}. Variant chr3-15644824-A-G is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.013572812). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.001 (1463/1461888) while in subpopulation SAS AF= 0.016 (1379/86258). AF 95% confidence interval is 0.0153. There are 24 homozygotes in gnomad4_exome. There are 1024 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 24 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTD	NM_001370658.1 linkuse as main transcript	c.908A>G	p.His303Arg	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 linkuse as main transcript	c.908A>G	p.His303Arg	missense_variant	4/4		NM_001370658.1	ENSP00000495254.2		P43251-4

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0149

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00205

AC:

516

AN:

251360

Hom.:

AF XY:

0.00280

AC XY:

380

AN XY:

135872

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:

0.0166

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.00100

AC:

1463

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

1024

AN XY:

727246

show subpopulations

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:

0.0160

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.00103

GnomAD4 genome

AF:

0.000486

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000711

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0147

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000513

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.00231

AC:

281

Asia WGS

AF:

0.00577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Biotinidase deficiency

Pathogenic:3Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 25, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 05, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 31, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2022	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 323 of the BTD protein (p.His323Arg). This variant is present in population databases (rs397507176, gnomAD 1.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with partial BTD deficiency who showed 10-30% of normal BTD enzymatic activity (PMID: 9654207, 26361991). ClinVar contains an entry for this variant (Variation ID: 38278). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BTD protein function. Experimental studies have shown that this missense change affects BTD function (PMID: 9654207, 24797656). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Aug 27, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 10, 2024	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with biotinidase deficiency (MIM#253260). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The condition associated with this gene is known to range from partial, with milder symptoms and later onset, to profound, with more severe symptoms and earlier onset. Also, individuals with the same genotype have been observed to have different clinical and biochemical phenotypes (PMIDs: 20301497, 28498829). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to arginine. (I) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD (v4) >=0.01 and <0.03 for a recessive condition (1489 heterozygotes, 24 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0600 - Variant is located in the annotated biotinidase_like domain (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in multiple individuals with a second reported BTD variant (phasing unclear), who were affected with partial biotinidase deficiency (10-30% of normal BTD enzymatic activity) (PMIDs: 35195902, 9654207, 26361991, 32300527, 38141137, 27329734). This variant has also been reported as likely pathogenic/pathogenic and as a VUS by clinical laboratories in ClinVar. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_001323582.1(BTD):c.1270G>C; p.(Asp424His)) in a recessive disease. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:2Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 15, 2022	The variant has been described in two heterozygous cases with a severe genotype (PMID: 33217065 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Taking into account the available information, we are unable to determine the clinical significance of this variant. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2024	The phenotype of individuals homozygous for p.(H303R) is unclear, as it is observed in apparent homozygous state in multiple unrelated individuals in large population cohorts (gnomAD) and healthy adult individuals tested at GeneDx; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.968A>G; p.(H323R); This variant is associated with the following publications: (PMID: 31191208, 24066991, 27535533, 28498829, 27657684, 27014582, 26810761, 22698809, 9654207, 26361991, 11668630, 32300527, 36684547, 35195902, 27329734, 17382128, 24797656) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 10, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	BTD: PM2, PM3, PP4:Moderate -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2021

The c.968A>G (p.H323R) alteration is located in coding exon 4 of the BTD gene. This alteration results from an A to G substitution at nucleotide position 968, causing the histidine (H) at amino acid position 323 to be replaced by an arginine (R). The BTD c.968A>G alteration has been reported previously in the compound heterozygous state in multiple individuals with enzyme levels consistent with partial biotinidase deficiency (Swango, 1998; Li, 2014, Gannavarapu, 2015; Wiltink, 2016; Mardhiah, 2020). The c.968A>G (p.H323R) alteration is considered a hypomorphic allele and only causes disease when in trans with a more severe allele (Lek, 2015). Based on the available evidence, this alteration is classified as likely pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 31, 2024

Variant summary: BTD c.908A>G (p.His303Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 251360 control chromosomes, predominantly at a frequency of 0.017 within the South Asian subpopulation in the gnomAD database, including 8 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3.72 fold of the estimated maximal expected allele frequency for a pathogenic variant in BTD causing Biotinidase Deficiency phenotype (0.0046). c.908A>G has been reported in the literature in individuals affected with Biotinidase Deficiency (e.g. Swango_1998, Al-Jasmi_2016, Mardhiah_2020, Karaoglan_2020, Forny_2022, Sharma_2024, Yilmaz_2024). These reports 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: 26589311, 9654207, 33217065, 32300527, 35195902, 38299772, 38141137). ClinVar contains an entry for this variant (Variation ID: 38278). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

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

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

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

MetaRNN

Benign

0.014

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

MetaSVM

Uncertain

0.22

MutationAssessor

Benign

1.6

.;.;L;.;.;.;.

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-5.5

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

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0020

.;D;.;T;.;D;D

Sift4G

Uncertain

0.0090

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

Polyphen

1.0

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

Vest4

0.85, 0.85, 0.84

MutPred

0.84

.;.;Loss of catalytic residue at M325 (P = 0.0612);.;.;.;.;

MVP

0.97

MPC

0.45

ClinPred

0.11

GERP RS

5.8

Varity_R

0.67

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

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