Variant 11-27055438-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003986.3(BBOX1):c.8G>C(p.Cys3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000545 in 1,609,374 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00056 ( 1 hom. )

Consequence

BBOX1
NM_003986.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.52

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.036743015).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBOX1	NM_003986.3 linkuse as main transcript	c.8G>C	p.Cys3Ser	missense_variant	3/9	ENST00000263182.8
BBOX1-AS1	NR_125768.1 linkuse as main transcript	n.378-8126C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBOX1	ENST00000263182.8 linkuse as main transcript	c.8G>C	p.Cys3Ser	missense_variant	3/9	5	NM_003986.3	P1
BBOX1-AS1	ENST00000526061.5 linkuse as main transcript	n.345-8126C>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000415

AC:

101

AN:

243252

Hom.:

AF XY:

0.000357

AC XY:

AN XY:

131684

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.0000604

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00122

Gnomad NFE exome

AF:

0.000597

Gnomad OTH exome

AF:

0.00101

GnomAD4 exome

AF:

0.000560

AC:

816

AN:

1457224

Hom.:

Cov.:

AF XY:

0.000480

AC XY:

348

AN XY:

724750

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.0000228

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00156

Gnomad4 NFE exome

AF:

0.000627

Gnomad4 OTH exome

AF:

0.000565

GnomAD4 genome

AF:

0.000401

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000944

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000340

Hom.:

Bravo

AF:

0.000283

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000404

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

Sep 15, 2021

The c.8G>C (p.C3S) alteration is located in exon 3 (coding exon 1) of the BBOX1 gene. This alteration results from a G to C substitution at nucleotide position 8, causing the cysteine (C) at amino acid position 3 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

0.092

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.25

Cadd

Benign

Dann

Benign

0.49

DEOGEN2

Benign

0.11

T;T;T;T;T

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.40

M_CAP

Benign

0.021

MetaRNN

Benign

0.037

T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.6

L;.;L;L;L

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

0.24

N;N;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.38

T;T;T;T;T

Sift4G

Benign

0.64

T;T;T;T;T

Polyphen

0.0010

B;.;B;B;B

Vest4

0.17

MutPred

0.29

Gain of disorder (P = 0.0042);Gain of disorder (P = 0.0042);Gain of disorder (P = 0.0042);Gain of disorder (P = 0.0042);Gain of disorder (P = 0.0042);

MVP

0.87

MPC

0.084

ClinPred

0.021

GERP RS

4.0

Varity_R

0.25

gMVP

0.56

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