chrX-43731723-G-A

Variant names:

• chrX-43731723-G-A
• rs138703731
• NM_000240.4:c.825G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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: Benign. The variant received -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 VariationId is 198701.
• BP7: Synonymous conserved (PhyloP=-0.037 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 67 XL gene

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.825G>A	p.Pro275Pro	synonymous	Exon 8 of 15	NP_000231.1
	MAOA	NM_001270458.2		c.426G>A	p.Pro142Pro	synonymous	Exon 9 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.825G>A	p.Pro275Pro	synonymous	Exon 8 of 15	ENSP00000340684.3
	MAOA	ENST00000967111.1		c.825G>A	p.Pro275Pro	synonymous	Exon 8 of 15	ENSP00000637170.1
	MAOA	ENST00000873971.1		c.825G>A	p.Pro275Pro	synonymous	Exon 8 of 15	ENSP00000544030.1

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 265 AN: 111583 Hom.: 0 Cov.: 23

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

GnomAD2 exomes AF: 0.00230 AC: 422 AN: 183199 AF XY: 0.00261

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 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

African (AFR) AF: 0.000606 AC: 16 AN: 26392

American (AMR) AF: 0.00148 AC: 52 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00454 AC: 88 AN: 19384

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30193

South Asian (SAS) AF: 0.00299 AC: 162 AN: 54137

European-Finnish (FIN) AF: 0.000148 AC: 6 AN: 40522

Middle Eastern (MID) AF: 0.00338 AC: 14 AN: 4136

European-Non Finnish (NFE) AF: 0.00436 AC: 3666 AN: 841667

Other (OTH) AF: 0.00347 AC: 160 AN: 46084

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

African (AFR) AF: 0.000521 AC: 16 AN: 30696

American (AMR) AF: 0.00191 AC: 20 AN: 10497

Ashkenazi Jewish (ASJ) AF: 0.00757 AC: 20 AN: 2643

East Asian (EAS) AF: 0.000283 AC: 1 AN: 3532

South Asian (SAS) AF: 0.00225 AC: 6 AN: 2664

European-Finnish (FIN) AF: 0.000166 AC: 1 AN: 6021

Middle Eastern (MID) AF: 0.00463 AC: 1 AN: 216

European-Non Finnish (NFE) AF: 0.00374 AC: 199 AN: 53165

Other (OTH) AF: 0.000660 AC: 1 AN: 1516

Alfa AF: 0.00277 Hom.: 44

Bravo AF: 0.00212

EpiCase AF: 0.00344

EpiControl AF: 0.00344

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	-	1	Brunner syndrome (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.73
DANN	Benign	0.43
PhyloP100		-0.037
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

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