Genetic Variant BBOX1:p.His179Tyr (chr11-27115453-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_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. 17/24 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

Publications

5 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003986.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BBOX1	NM_003986.3	MANE Select	c.535C>T	p.His179Tyr	missense splice_region	Exon 6 of 9	NP_003977.1	O75936
BBOX1	NM_001376258.1		c.535C>T	p.His179Tyr	missense splice_region	Exon 6 of 9	NP_001363187.1	O75936
BBOX1	NM_001376259.1		c.535C>T	p.His179Tyr	missense splice_region	Exon 6 of 9	NP_001363188.1	O75936

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BBOX1	ENST00000263182.8	TSL:5 MANE Select	c.535C>T	p.His179Tyr	missense splice_region	Exon 6 of 9	ENSP00000263182.3	O75936
BBOX1	ENST00000525090.1	TSL:1	c.535C>T	p.His179Tyr	missense splice_region	Exon 4 of 7	ENSP00000433772.1	O75936
BBOX1	ENST00000528583.5	TSL:1	c.535C>T	p.His179Tyr	missense splice_region	Exon 5 of 8	ENSP00000434918.1	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

GnomAD2 exomes

AF:

0.000271

AC:

AN:

246988

AF XY:

0.000217

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 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

African (AFR)

AF:

0.0000303

AC:

AN:

32996

American (AMR)

AF:

0.000341

AC:

AN:

43974

Ashkenazi Jewish (ASJ)

AF:

0.0000386

AC:

AN:

25906

East Asian (EAS)

AF:

0.00

AC:

AN:

39434

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85650

European-Finnish (FIN)

AF:

0.0000751

AC:

AN:

53244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.000564

AC:

625

AN:

1108650

Other (OTH)

AF:

0.000450

AC:

AN:

60064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

117

146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000283

AC:

AN:

151872

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74182

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41410

American (AMR)

AF:

0.000329

AC:

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000457

AC:

AN:

67882

Other (OTH)

AF:

0.000480

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.18

Eigen

Benign

-0.060

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.83

M_CAP

Benign

0.011

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.64

MutationAssessor

Benign

1.2

PhyloP100

5.3

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.7

REVEL

Benign

0.20

Sift

Benign

1.0

Sift4G

Benign

0.61

Polyphen

0.0070

Vest4

0.42

MVP

0.92

MPC

0.084

ClinPred

0.035

GERP RS

5.3

Varity_R

0.36

gMVP

0.53

Mutation Taster

=58/42

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over