chrX-43728184-G-A

Variant names:

• chrX-43728184-G-A
• rs58524323
• NM_000240.4:c.515G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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:5
• Conservation: PhyloP100: 1.10
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 435814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 58 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAOA	NM_000240.4	MANE Select	c.515G>A	p.Arg172Gln	missense	Exon 6 of 15	NP_000231.1	Q53YE7
	MAOA	NM_001270458.2		c.116G>A	p.Arg39Gln	missense	Exon 7 of 16	NP_001257387.1	P21397-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAOA	ENST00000338702.4	TSL:1 MANE Select	c.515G>A	p.Arg172Gln	missense	Exon 6 of 15	ENSP00000340684.3	P21397-1
	MAOA	ENST00000967111.1		c.515G>A	p.Arg172Gln	missense	Exon 6 of 15	ENSP00000637170.1
	MAOA	ENST00000873971.1		c.515G>A	p.Arg172Gln	missense	Exon 6 of 15	ENSP00000544030.1

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 228 AN: 111652 Hom.: 0 Cov.: 24

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

GnomAD2 exomes AF: 0.000622 AC: 114 AN: 183193 AF XY: 0.000354

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 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

African (AFR) AF: 0.00800 AC: 211 AN: 26386

American (AMR) AF: 0.000511 AC: 18 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19380

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30202

South Asian (SAS) AF: 0.000111 AC: 6 AN: 54116

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40529

Middle Eastern (MID) AF: 0.000967 AC: 4 AN: 4135

European-Non Finnish (NFE) AF: 0.00000832 AC: 7 AN: 841183

Other (OTH) AF: 0.000608 AC: 28 AN: 46075

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

African (AFR) AF: 0.00683 AC: 210 AN: 30731

American (AMR) AF: 0.00142 AC: 15 AN: 10553

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3558

South Asian (SAS) AF: 0.00 AC: 0 AN: 2659

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53144

Other (OTH) AF: 0.000658 AC: 1 AN: 1519

Alfa AF: 0.000929 Hom.: 45

Bravo AF: 0.00286

ESP6500AA AF: 0.00600 AC: 23

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000585 AC: 71

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Brunner syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	MAOA-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Uncertain	0.43	T
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.075	N
PhyloP100		1.1
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.074
Sift	Benign	0.94	T
Sift4G	Benign	0.64	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
Mutation Taster		=88/12	polymorphism

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: rs58524323; hg19: chrX-43587431;