11-27055639-A-T

Variant summary

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

The NM_003986.3(BBOX1):c.209A>T(p.Asp70Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 6.76

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBOX1	NM_003986.3	c.209A>T	p.Asp70Val	missense_variant	3/9	ENST00000263182.8
BBOX1-AS1	NR_125768.1	n.378-8327T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBOX1	ENST00000263182.8	c.209A>T	p.Asp70Val	missense_variant	3/9	5	NM_003986.3	P1
BBOX1-AS1	ENST00000526061.5	n.345-8327T>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Aug 10, 2023

The c.209A>T (p.D70V) alteration is located in exon 3 (coding exon 1) of the BBOX1 gene. This alteration results from a A to T substitution at nucleotide position 209, causing the aspartic acid (D) at amino acid position 70 to be replaced by a valine (V). 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	Uncertain	0.37
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.41	T;T;T;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.096	D
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Uncertain	0.0032	D
MutationAssessor	Uncertain	2.5	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.035	D;D;D;D
Polyphen		0.63	P;P;P;P
Vest4		0.54
MutPred		0.56		Loss of ubiquitination at K72 (P = 0.0435);Loss of ubiquitination at K72 (P = 0.0435);Loss of ubiquitination at K72 (P = 0.0435);Loss of ubiquitination at K72 (P = 0.0435);
MVP		0.94
MPC		0.23
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.69
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr11-27077186;