6-20112994-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001080480.3(MBOAT1):c.1091G>A(p.Arg364Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000219 in 1,461,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R364L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: MBOAT1 NM_001080480.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.98

Genes affected

MBOAT1 (HGNC:21579): (membrane bound O-acyltransferase domain containing 1) This gene belongs to the membrane-bound O-acetyltransferase superfamily. The encoded transmembrane protein is an enzyme that transfers organic compounds, preferably from oleoyl-CoA, to hydroxyl groups of protein targets in membranes. A translocation disrupting this gene may be associated with brachydactyly syndactyly syndrome. Alternately spliced transcript variants have been described for this gene. [provided by RefSeq, Nov 2012]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MBOAT1	NM_001080480.3	c.1091G>A	p.Arg364Gln	missense_variant	11/13	ENST00000324607.8
MBOAT1	XM_006714999.3	c.995G>A	p.Arg332Gln	missense_variant	11/13
MBOAT1	NR_073465.2	n.1046G>A		non_coding_transcript_exon_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MBOAT1	ENST00000324607.8	c.1091G>A	p.Arg364Gln	missense_variant	11/13	1	NM_001080480.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250724 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135470

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461548 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727070

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

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

Jan 02, 2024

The c.1091G>A (p.R364Q) alteration is located in exon 11 (coding exon 11) of the MBOAT1 gene. This alteration results from a G to A substitution at nucleotide position 1091, causing the arginine (R) at amino acid position 364 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	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.87		Loss of solvent accessibility (P = 0.1077);
MVP		0.88
MPC		0.29
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.34
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs143520373; hg19: chr6-20113225;