Variant 11-27115453-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003986.3(BBOX1):c.535C>T(p.His179Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000446 in 1,607,508 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00046 ( 1 hom. )

Consequence

BBOX1
NM_003986.3 missense, splice_region

Scores

Splicing: ADA: 0.004260

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.35

Variant links:

Genes affected

BBOX1 (HGNC:964): (gamma-butyrobetaine hydroxylase 1) This gene encodes gamma butyrobetaine hydroxylase which catalyzes the formation of L-carnitine from gamma-butyrobetaine, the last step in the L-carnitine biosynthetic pathway. Carnitine is essential for the transport of activated fatty acids across the mitochondrial membrane during mitochondrial beta-oxidation. [provided by RefSeq, Jul 2008]

BBOX1 links:

BBOX1-AS1 (HGNC:50700): (BBOX1 antisense RNA 1)

BBOX1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1439819).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBOX1	NM_003986.3 link	c.535C>T	p.His179Tyr	missense_variant, splice_region_variant	6/9	ENST00000263182.8	NP_003977.1	O75936

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBOX1	ENST00000263182.8 link	c.535C>T	p.His179Tyr	missense_variant, splice_region_variant	6/9	5	NM_003986.3	ENSP00000263182.3		O75936

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

151872

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000329

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:

0.000457

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000271

AC:

AN:

246988

Hom.:

AF XY:

0.000217

AC XY:

AN XY:

133624

show subpopulations

Gnomad AFR exome

AF:

0.0000630

Gnomad AMR exome

AF:

0.000328

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000333

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.000437

Gnomad OTH exome

AF:

0.000334

GnomAD4 exome

AF:

0.000463

AC:

674

AN:

1455636

Hom.:

Cov.:

AF XY:

0.000425

AC XY:

308

AN XY:

724182

show subpopulations

Gnomad4 AFR exome

AF:

0.0000303

Gnomad4 AMR exome

AF:

0.000341

Gnomad4 ASJ exome

AF:

0.0000386

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.0000751

Gnomad4 NFE exome

AF:

0.000564

Gnomad4 OTH exome

AF:

0.000450

GnomAD4 genome

AF:

0.000283

AC:

AN:

151872

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74182

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.000329

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000457

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.000482

Hom.:

Bravo

AF:

0.000336

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000255

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 06, 2023

The c.535C>T (p.H179Y) alteration is located in exon 6 (coding exon 4) of the BBOX1 gene. This alteration results from a C to T substitution at nucleotide position 535, causing the histidine (H) at amino acid position 179 to be replaced by a tyrosine (Y). 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

0.11

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.18

T;T;T;T

Eigen

Benign

-0.060

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.83

.;T;.;.

M_CAP

Benign

0.011

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

1.2

L;L;L;L

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.7

N;N;N;N

REVEL

Benign

0.20

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

0.61

T;T;T;T

Polyphen

0.0070

B;B;B;B

Vest4

0.42

MVP

0.92

MPC

0.084

ClinPred

0.035

GERP RS

5.3

Varity_R

0.36

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0043

dbscSNV1_RF

Benign

0.024

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