rs771740634

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000240.4(MAOA):c.402G>A(p.Met134Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000513 in 1,168,470 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. 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. M134V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000038 ( 0 hom. 2 hem. )

Consequence

MAOA
NM_000240.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.87

Publications

0 publications found

Variant links:

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)

MAOA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAOA	NM_000240.4 link	c.402G>A	p.Met134Ile	missense_variant	Exon 4 of 15	ENST00000338702.4	NP_000231.1	P21397-1Q53YE7Q49A63
MAOA	NM_001270458.2 link	c.3G>A	p.Met1?	start_lost	Exon 5 of 16		NP_001257387.1	P21397-2Q49A63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAOA	ENST00000338702.4 link	c.402G>A	p.Met134Ile	missense_variant	Exon 4 of 15	1	NM_000240.4	ENSP00000340684.3		P21397-1

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111573

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183090

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000245

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000378

AC:

AN:

1056897

Hom.:

Cov.:

AF XY:

0.00000613

AC XY:

AN XY:

326109

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25458

American (AMR)

AF:

0.00

AC:

AN:

35158

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19128

East Asian (EAS)

AF:

0.00

AC:

AN:

30067

South Asian (SAS)

AF:

0.00

AC:

AN:

53223

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40462

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4020

European-Non Finnish (NFE)

AF:

0.00000497

AC:

AN:

804627

Other (OTH)

AF:

0.00

AC:

AN:

44754

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111573

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33757

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30645

American (AMR)

AF:

0.00

AC:

AN:

10434

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2637

East Asian (EAS)

AF:

0.00

AC:

AN:

3579

South Asian (SAS)

AF:

0.00

AC:

AN:

2643

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6068

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

53150

Other (OTH)

AF:

0.00

AC:

AN:

1497

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 20, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.402G>A (p.M134I) alteration is located in exon 4 (coding exon 4) of the MAOA gene. This alteration results from a G to A substitution at nucleotide position 402, causing the methionine (M) at amino acid position 134 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Brunner syndrome

Uncertain:1

Jun 20, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MAOA-related disease. This variant is present in population databases (rs771740634, ExAC 0.004%). This sequence change replaces methionine with isoleucine at codon 134 of the MAOA protein (p.Met134Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.78

.;D

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.29

MetaRNN

Uncertain

0.63

D;T

MetaSVM

Uncertain

0.49

MutationAssessor

Uncertain

2.2

.;M

PhyloP100

4.9

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.7

D;D

REVEL

Uncertain

0.43

Sift

Uncertain

0.0080

D;D

Sift4G

Uncertain

0.018

D;D

Polyphen

0.60

.;P

Vest4

0.70

MutPred

0.64

.;Loss of disorder (P = 0.1186);

MVP

0.94

MPC

1.1

ClinPred

0.63

GERP RS

5.5

Varity_R

0.87

gMVP

0.86

Mutation Taster

=20/180

disease causing

(source)

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

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rs771740634

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over