X-43736253-G-T

Variant names:

• chrX-43736253-G-T
• rs755359800
• NM_000240.4:c.1079G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000240.4(MAOA):​c.1079G>T​(p.Arg360Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000926 in 1,080,273 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R360Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.3e-7 (0 hom. 0 hem.)
• Consequence: MAOA NM_000240.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.831
• Publications: 0 publications found

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]

MAOA Gene-Disease associations (from GenCC):

• Brunner syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17361403).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000240.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAOA	NM_000240.4	MANE Select	c.1079G>T	p.Arg360Leu	missense	Exon 10 of 15	NP_000231.1
	MAOA	NM_001270458.2		c.680G>T	p.Arg227Leu	missense	Exon 11 of 16	NP_001257387.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAOA	ENST00000338702.4	TSL:1 MANE Select	c.1079G>T	p.Arg360Leu	missense	Exon 10 of 15	ENSP00000340684.3
	MAOA	ENST00000693128.1		c.974G>T	p.Arg325Leu	missense	Exon 9 of 14	ENSP00000508493.1
	MAOA	ENST00000542639.6	TSL:2	c.680G>T	p.Arg227Leu	missense	Exon 11 of 16	ENSP00000440846.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.26e-7 AC: 1 AN: 1080273 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 347701

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26025

American (AMR) AF: 0.00 AC: 0 AN: 34838

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18981

East Asian (EAS) AF: 0.00 AC: 0 AN: 29535

South Asian (SAS) AF: 0.00 AC: 0 AN: 53256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39529

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4063

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 828862

Other (OTH) AF: 0.0000221 AC: 1 AN: 45184

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.78	D
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.83
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.14
Sift	Benign	0.11	T
Sift4G	Benign	0.18	T
Polyphen		0.0030	B
Vest4		0.18
MutPred		0.42		Loss of MoRF binding (P = 0.015)
MVP		0.73
MPC		0.84
ClinPred		0.21	T
GERP RS		1.3
Varity_R		0.45
gMVP		0.94
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs755359800; hg19: chrX-43595500;