rs138703731

Positions:

• chrX-43731723-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000240.4(MAOA):​c.825G>A​(p.Pro275Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00366 in 1,209,353 control chromosomes in the GnomAD database, including 4 homozygotes. There are 1,421 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., 67 hem., cov: 23)
  • Exomes 𝑓: 0.0038 (4 hom. 1354 hem.)
• Consequence: MAOA NM_000240.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.0370

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-43731723-G-A is Benign according to our data. Variant chrX-43731723-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198701.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}. Variant chrX-43731723-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.037 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 67 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAOA	NM_000240.4	c.825G>A	p.Pro275Pro	synonymous_variant	8/15	ENST00000338702.4	NP_000231.1
MAOA	NM_001270458.2	c.426G>A	p.Pro142Pro	synonymous_variant	9/16		NP_001257387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAOA	ENST00000338702.4	c.825G>A	p.Pro275Pro	synonymous_variant	8/15	1	NM_000240.4	ENSP00000340684.3

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 265 AN: 111583 Hom.: 0 Cov.: 23 AF XY: 0.00198 AC XY: 67 AN XY: 33787

Gnomad AFR AF: 0.000522

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00191

Gnomad ASJ AF: 0.00757

Gnomad EAS AF: 0.000282

Gnomad SAS AF: 0.00225

Gnomad FIN AF: 0.000166

Gnomad MID AF: 0.00422

Gnomad NFE AF: 0.00374

Gnomad OTH AF: 0.000668

GnomAD3 exomes AF: 0.00230 AC: 422 AN: 183199 Hom.: 0 AF XY: 0.00261 AC XY: 177 AN XY: 67753

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.00164

Gnomad ASJ exome AF: 0.00428

Gnomad EAS exome AF: 0.0000723

Gnomad SAS exome AF: 0.00346

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00319

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00379 AC: 4165 AN: 1097719 Hom.: 4 Cov.: 30 AF XY: 0.00373 AC XY: 1354 AN XY: 363107

Gnomad4 AFR exome AF: 0.000606

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00454

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00299

Gnomad4 FIN exome AF: 0.000148

Gnomad4 NFE exome AF: 0.00436

Gnomad4 OTH exome AF: 0.00347

GnomAD4 genome AF: 0.00237 AC: 265 AN: 111634 Hom.: 0 Cov.: 23 AF XY: 0.00198 AC XY: 67 AN XY: 33848

Gnomad4 AFR AF: 0.000521

Gnomad4 AMR AF: 0.00191

Gnomad4 ASJ AF: 0.00757

Gnomad4 EAS AF: 0.000283

Gnomad4 SAS AF: 0.00225

Gnomad4 FIN AF: 0.000166

Gnomad4 NFE AF: 0.00374

Gnomad4 OTH AF: 0.000660

Alfa AF: 0.00298 Hom.: 25

Bravo AF: 0.00212

EpiCase AF: 0.00344

EpiControl AF: 0.00344

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 24, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 10, 2015	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2016

This alteration is classified as likely 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

Labcorp Genetics (formerly Invitae), Labcorp

Dec 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.73
DANN	Benign	0.43

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: rs138703731; hg19: chrX-43590970; COSMIC: COSV58640894; COSMIC: COSV58640894;