3-15644736-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM1BP4_StrongBP6_Very_StrongBS1BS2_Supporting

The NM_001370658.1(BTD):ā€‹c.820A>Gā€‹(p.Ile274Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,614,190 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.011 ( 40 hom., cov: 32)
Exomes š‘“: 0.0012 ( 34 hom. )

Consequence

BTD
NM_001370658.1 missense

Scores

1
17

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.0220
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001370658.1
BP4
Computational evidence support a benign effect (MetaRNN=0.006632507).
BP6
Variant 3-15644736-A-G is Benign according to our data. Variant chr3-15644736-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 25047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15644736-A-G is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0109 (1663/152296) while in subpopulation AFR AF= 0.0384 (1594/41558). AF 95% confidence interval is 0.0368. There are 40 homozygotes in gnomad4. There are 794 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 40 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 UniProt
BTDNM_001370658.1 linkuse as main transcriptc.820A>G p.Ile274Val missense_variant 4/4 ENST00000643237.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BTDENST00000643237.3 linkuse as main transcriptc.820A>G p.Ile274Val missense_variant 4/4 NM_001370658.1 P1P43251-4

Frequencies

GnomAD3 genomes
AF:
0.0109
AC:
1654
AN:
152178
Hom.:
40
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0383
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00360
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:
0.0000441
Gnomad OTH
AF:
0.00527
GnomAD3 exomes
AF:
0.00324
AC:
814
AN:
251404
Hom.:
16
AF XY:
0.00230
AC XY:
313
AN XY:
135868
show subpopulations
Gnomad AFR exome
AF:
0.0423
Gnomad AMR exome
AF:
0.00298
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000229
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000106
Gnomad OTH exome
AF:
0.000652
GnomAD4 exome
AF:
0.00123
AC:
1796
AN:
1461894
Hom.:
34
Cov.:
31
AF XY:
0.00105
AC XY:
767
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.0422
Gnomad4 AMR exome
AF:
0.00320
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000209
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000504
Gnomad4 OTH exome
AF:
0.00248
GnomAD4 genome
AF:
0.0109
AC:
1663
AN:
152296
Hom.:
40
Cov.:
32
AF XY:
0.0107
AC XY:
794
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.0384
Gnomad4 AMR
AF:
0.00359
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00521
Alfa
AF:
0.00177
Hom.:
8
Bravo
AF:
0.0129
ESP6500AA
AF:
0.0395
AC:
174
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00396
AC:
481
Asia WGS
AF:
0.00144
AC:
5
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.000178

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Biotinidase deficiency Benign:7
Likely benign, criteria provided, single submitterclinical testingPars Genome LabMay 18, 2021- -
Benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterApr 04, 2024- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Likely benign, criteria provided, single submitterclinical testingCounsylJun 06, 2018- -
Likely benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Benign, no assertion criteria providedclinical testingNatera, Inc.Oct 30, 2019- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
not provided Benign:4
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2024BTD: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJul 30, 2021- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsSep 28, 2015- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 17, 2022Variant summary: BTD c.820A>G (p.Ile274Val) 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 0.0032 in 251404 control chromosomes, predominantly at a frequency of 0.042 within the African or African-American subpopulation in the gnomAD database, including 15 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 9.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in BTD causing Biotinidase Deficiency phenotype (0.0046), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
BTD-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 20, 2023This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.068
BayesDel_addAF
Benign
-0.58
T
BayesDel_noAF
Benign
-0.58
CADD
Benign
0.018
DANN
Benign
0.21
DEOGEN2
Benign
0.27
.;.;T;.;.;.;.
Eigen
Benign
-1.9
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.0063
N
LIST_S2
Benign
0.60
.;T;T;.;.;T;T
MetaRNN
Benign
0.0066
T;T;T;T;T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
-1.1
.;.;N;.;.;.;.
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.26
T
PROVEAN
Benign
0.64
.;N;.;.;.;N;N
REVEL
Uncertain
0.32
Sift
Benign
1.0
.;T;.;.;.;T;T
Sift4G
Benign
1.0
.;T;.;.;.;T;T
Polyphen
0.0
.;.;B;.;.;.;.
Vest4
0.049, 0.030, 0.032
MVP
0.50
MPC
0.061
ClinPred
0.0019
T
GERP RS
-4.3
Varity_R
0.016
gMVP
0.67

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: rs35976361; hg19: chr3-15686243; COSMIC: COSV99068531; COSMIC: COSV99068531; API