rs6323

Variant names:

• chrX-43731789-G-T
• rs6323
• NM_000240.4:c.891G>T
• MAOA p.Arg297Arg

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-9 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -9 classification points (ACMG Germline Pathogenicity v2019). BP4_StrongBP6_StrongBP7

The NM_000240.4(MAOA):c.891G>T (p.Arg297Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. No reliable population frequency data is available for this variant in the gnomAD database. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (21051 hom., 22800 hem., cov: 23)
  • Exomes 𝑓: 0.68 (177110 hom. 243137 hem.)
  • Failed GnomAD Quality Control
• Consequence: MAOA NM_000240.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.300
• Publications: 148 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), PanelApp Australia

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -9 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000240.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MAOA NM_000240.4	MANE Select	c.891G>T p.Arg297Arg	synonymous	Exon 8 of 15	Prot: NP_000231.1 UniProt:
	MAOA NM_001270458.2		c.492G>T p.Arg164Arg	synonymous	Exon 9 of 16	Prot: NP_001257387.1 UniProt:

MAOA NM_000240.4

MANE Select

HGVSc / HGVSpc.891G>Tp.Arg297Arg

Exon rankExon 8 of 15

synonymous

Prot: NP_000231.1UniProt: Q53YE7P21397-1

MAOA NM_001270458.2

HGVSc / HGVSpc.492G>Tp.Arg164Arg

Exon rankExon 9 of 16

synonymous

Prot: NP_001257387.1UniProt: P21397-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MAOA ENST00000338702.4	TSL:1MANE Select	c.891G>T p.Arg297Arg	synonymous	Exon 8 of 15	Prot: ENSP00000340684.3 UniProt:
	MAOA ENST00000967111.1		c.891G>T p.Arg297Arg	synonymous	Exon 8 of 15	Prot: ENSP00000637170.1 UniProt:
	MAOA ENST00000873971.1		c.891G>T p.Arg297Arg	synonymous	Exon 8 of 15	Prot: ENSP00000544030.1 UniProt:

MAOA ENST00000338702.4

TSL:1MANE Select

HGVSc / HGVSpc.891G>Tp.Arg297Arg

Exon rankExon 8 of 15

synonymous

Prot: ENSP00000340684.3UniProt: P21397-1

MAOA ENST00000967111.1

HGVSc / HGVSpc.891G>Tp.Arg297Arg

Exon rankExon 8 of 15

synonymous

Prot: ENSP00000637170.1UniProt: A0ACI8VKS4

MAOA ENST00000873971.1

HGVSc / HGVSpc.891G>Tp.Arg297Arg

Exon rankExon 8 of 15

synonymous

Prot: ENSP00000544030.1UniProt: A0ACI8R2S8

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.722	AC:79528	Hom:21051	AN:110183	Cov:23
GnomAD2 exomes	AF: 0.650	AC:118872	Hom:	AN:182873	Cov:
GnomAD4 exome Warning	AF: 0.684	AC:749816	Hom:177110	AN:1096495	Cov:34
GnomAD4 genome Warning	AF: 0.722	AC:79570	Hom:21051	AN:110234	Cov:23
TOPMed (Bravo)	AF: 0.735	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.718	AC:220456	Hom:93766	AN:307138	Cov:
Local & regional cohorts 8 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.749	AC:1434	Hom:422	AN:1914	Cov:
Denmark Genome	AF: 0.697	AC:161	Hom:	AN:231	Cov:
ESP6500 (Exome Variant Server)	AF: 0.758	AC:8012	Hom:	AN:10563	Cov:
Korea4K (4,157 Koreans)	AF: 0.436	AC:2276	Hom:	AN:5222	Cov:
Qatari Genome	AF: 0.750	AC:875	Hom:	AN:1166	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.418	AC:42629	Hom:7241	AN:102064	Cov:
Turkish Variome	AF: 0.676	AC:4509	Hom:1883	AN:6674	Cov:
UK10K	AF: 0.705	AC:4648	Hom:	AN:6597	Cov:

Showing 14 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.693 *	4758	6867	0.684 *	8367	12227
BipEx(Bipolar disorder (including schizoaffective))	0.700	19899	28420	0.698	20139	28844
Epi25(Epilepsy)	0.683	28644	41952	0.710	47481	66874
SCHEMA(Schizophrenia)	0.668	61796	92529	0.693	109978	158627

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	8.7
BayesDel_noAF	Benign	-0.56
CADD	Benign	4.2
DANN	Benign	0.58
GPN-Star LLR	N/A	7.4
GPN-Star score	N/A	3.1
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	0.30

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs6323;

hg19: chrX-43591036;

COSMIC: COSV58641947;

COSMIC: COSV58641947;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar