rs58524323

chrX-43728184-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000240.4(MAOA):c.515G>A(p.Arg172Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000419 in 1,208,915 control chromosomes in the GnomAD database, including 2 homozygotes. There are 145 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., 58 hem., cov: 24)
  • Exomes 𝑓: 0.00025 (2 hom. 87 hem.)
• Consequence: MAOA NM_000240.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.10

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006507039).
• BP6: Variant X-43728184-G-A is Benign according to our data. Variant chrX-43728184-G-A is described in ClinVar as [Benign]. Clinvar id is 435814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-43728184-G-A is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 58 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAOA	NM_000240.4	c.515G>A	p.Arg172Gln	missense_variant	6/15	ENST00000338702.4
MAOA	NM_001270458.2	c.116G>A	p.Arg39Gln	missense_variant	7/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAOA	ENST00000338702.4	c.515G>A	p.Arg172Gln	missense_variant	6/15	1	NM_000240.4	P1

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 228 AN: 111652 Hom.: 0 Cov.: 24 AF XY: 0.00171 AC XY: 58 AN XY: 33834

Gnomad AFR AF: 0.00685

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00142

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.000667

GnomAD3 exomes AF: 0.000622 AC: 114 AN: 183193 Hom.: 0 AF XY: 0.000354 AC XY: 24 AN XY: 67701

Gnomad AFR exome AF: 0.00730

Gnomad AMR exome AF: 0.000437

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.000442

GnomAD4 exome AF: 0.000253 AC: 278 AN: 1097212 Hom.: 2 Cov.: 30 AF XY: 0.000240 AC XY: 87 AN XY: 362620

Gnomad4 AFR exome AF: 0.00800

Gnomad4 AMR exome AF: 0.000511

Gnomad4 ASJ exome AF: 0.0000516

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.00000832

Gnomad4 OTH exome AF: 0.000608

GnomAD4 genome AF: 0.00204 AC: 228 AN: 111703 Hom.: 0 Cov.: 24 AF XY: 0.00171 AC XY: 58 AN XY: 33895

Gnomad4 AFR AF: 0.00683

Gnomad4 AMR AF: 0.00142

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.000658

Alfa AF: 0.000346 Hom.: 17

Bravo AF: 0.00286

ESP6500AA AF: 0.00600 AC: 23

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000585 AC: 71

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 30, 2016

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Brunner syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

MAOA-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	1.0
Dann	Benign	0.55
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.0065	T;T
MetaSVM	Benign	-0.65	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.18	N;N
REVEL	Benign	0.074
Sift	Benign	0.94	T;T
Sift4G	Benign	0.64	T;T
Polyphen		0.0010	.;B
Vest4		0.034
MVP		0.66
MPC		0.78
ClinPred		0.0021	T
GERP RS		-2.7
Varity_R		0.083
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs58524323; hg19: chrX-43587431;