NM_003986.3:c.399T>G

Variant names:

• chr11-27093232-T-G
• rs143972595
• NM_003986.3:c.399T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003986.3(BBOX1):​c.399T>G​(p.Tyr133*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y133Y) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BBOX1 NM_003986.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.849
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBOX1	NM_003986.3	MANE Select	c.399T>G	p.Tyr133*	stop_gained	Exon 5 of 9	NP_003977.1	O75936
	BBOX1	NM_001376258.1		c.399T>G	p.Tyr133*	stop_gained	Exon 5 of 9	NP_001363187.1	O75936
	BBOX1	NM_001376259.1		c.399T>G	p.Tyr133*	stop_gained	Exon 5 of 9	NP_001363188.1	O75936

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBOX1	ENST00000263182.8	TSL:5 MANE Select	c.399T>G	p.Tyr133*	stop_gained	Exon 5 of 9	ENSP00000263182.3	O75936
	BBOX1	ENST00000525090.1	TSL:1	c.399T>G	p.Tyr133*	stop_gained	Exon 3 of 7	ENSP00000433772.1	O75936
	BBOX1	ENST00000528583.5	TSL:1	c.399T>G	p.Tyr133*	stop_gained	Exon 4 of 8	ENSP00000434918.1	O75936

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Benign	0.16
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.52	D
PhyloP100		0.85
Vest4		0.44
GERP RS		0.28
Mutation Taster		=6/194	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs143972595; hg19: chr11-27114779;