11-27093241-C-A

Position:

• chr11-27093241-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003986.3(BBOX1):​c.408C>A​(p.His136Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: BBOX1 NM_003986.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.692

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

ACMG classification

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=0.13196597).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBOX1	NM_003986.3	c.408C>A	p.His136Gln	missense_variant	5/9	ENST00000263182.8	NP_003977.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBOX1	ENST00000263182.8	c.408C>A	p.His136Gln	missense_variant	5/9	5	NM_003986.3	ENSP00000263182.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 24, 2024

The c.408C>A (p.H136Q) alteration is located in exon 5 (coding exon 3) of the BBOX1 gene. This alteration results from a C to A substitution at nucleotide position 408, causing the histidine (H) at amino acid position 136 to be replaced by a glutamine (Q). 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	0.13
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.0040
DANN	Benign	0.56
DEOGEN2	Benign	0.099	T;T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.62	.;T;.;.
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.14	N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.62	N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.50	T;T;T;T
Sift4G	Benign	0.63	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.19
MutPred		0.56		Gain of MoRF binding (P = 0.0891);Gain of MoRF binding (P = 0.0891);Gain of MoRF binding (P = 0.0891);Gain of MoRF binding (P = 0.0891);
MVP		0.80
MPC		0.070
ClinPred		0.048	T
GERP RS		0.47
Varity_R		0.099
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-27114788;