X-43693353-C-CT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000240.4(MAOA):c.233dup(p.Leu78PhefsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MAOA NM_000240.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.04

Genes affected

MAOA (HGNC:6833): (monoamine oxidase A) This gene is one of two neighboring gene family members that encode mitochondrial enzymes which catalyze the oxidative deamination of amines, such as dopamine, norepinephrine, and serotonin. Mutation of this gene results in Brunner syndrome. This gene has also been associated with a variety of other psychiatric disorders, including antisocial behavior. Alternatively spliced transcript variants encoding multiple isoforms have been observed. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-43693353-C-CT is Pathogenic according to our data. Variant chrX-43693353-C-CT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 992787.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAOA	NM_000240.4	c.233dup	p.Leu78PhefsTer5	frameshift_variant	3/15	ENST00000338702.4
MAOA	NM_001270458.2	c.-167dup		5_prime_UTR_variant	4/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAOA	ENST00000338702.4	c.233dup	p.Leu78PhefsTer5	frameshift_variant	3/15	1	NM_000240.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

Jul 17, 2019

The c.233dup (p.Leu78PhefsTer5) variant identified in the MAOA gene is a duplication of a single nucleotide resulting in a frameshift of the protein at amino acid 78/528 (coding exon 3/15), which is predicted to lead to a premature stop codon approximately 5 amino acids downstream. This variant is absent in gnomAD and ExAC, suggesting that it is not a common benign variant in the populations represented in these databases. The c.233dup (p.Leu78PhefsTer5) variant is absent from ClinVar and to our current knowledge has not been reported in affected individuals in the literature, however other nonsense and frameshift variants have been observed in individuals with Brunner syndrome [PMID: 8211186, PMID: 25807999], and mouse models also suggest loss of function to be the mechanism of pathogenicity [PMID: 7792602]. Given its deleterious nature and absence in population databases, the hemizygous c.233dup (p.Leu78PhefsTer5) variant identified is reported here as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs2033551253; hg19: chrX-43552600;