chrX-43744144-T-C

Variant names:

• chrX-43744144-T-C
• rs1137070
• NM_000240.4:c.1410T>C
• MAOA p.Asp470Asp

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.1410T>C (p.Asp470Asp) 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 0.65 (16929 hom., 19972 hem., cov: 21)
  • Exomes 𝑓: 0.67 (171518 hom. 239866 hem.)
  • Failed GnomAD Quality Control
• Consequence: MAOA NM_000240.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.140
• Publications: 123 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.1410T>C p.Asp470Asp	synonymous	Exon 14 of 15	Prot: NP_000231.1 UniProt:
	MAOA NM_001270458.2		c.1011T>C p.Asp337Asp	synonymous	Exon 15 of 16	Prot: NP_001257387.1 UniProt:

MAOA NM_000240.4

MANE Select

HGVSc / HGVSpc.1410T>Cp.Asp470Asp

Exon rankExon 14 of 15

synonymous

Prot: NP_000231.1UniProt: Q53YE7P21397-1

MAOA NM_001270458.2

HGVSc / HGVSpc.1011T>Cp.Asp337Asp

Exon rankExon 15 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.1410T>C p.Asp470Asp	synonymous	Exon 14 of 15	Prot: ENSP00000340684.3 UniProt:
	MAOA ENST00000967111.1		c.1473T>C p.Asp491Asp	synonymous	Exon 14 of 15	Prot: ENSP00000637170.1 UniProt:
	MAOA ENST00000873971.1		c.1452T>C p.Asp484Asp	synonymous	Exon 14 of 15	Prot: ENSP00000544030.1 UniProt:

MAOA ENST00000338702.4

TSL:1MANE Select

HGVSc / HGVSpc.1410T>Cp.Asp470Asp

Exon rankExon 14 of 15

synonymous

Prot: ENSP00000340684.3UniProt: P21397-1

MAOA ENST00000967111.1

HGVSc / HGVSpc.1473T>Cp.Asp491Asp

Exon rankExon 14 of 15

synonymous

Prot: ENSP00000637170.1UniProt: A0ACI8VKS4

MAOA ENST00000873971.1

HGVSc / HGVSpc.1452T>Cp.Asp484Asp

Exon rankExon 14 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: 0.650	AC:71036	Hom:16932	AN:109333	Cov:21
GnomAD2 exomes	AF: 0.621	AC:113389	Hom:	AN:182565	Cov:
GnomAD4 exome Warning	AF: 0.673	AC:738410	Hom:171518	AN:1096387	Cov:36
GnomAD4 genome Warning	AF: 0.650	AC:71065	Hom:16929	AN:109385	Cov:21
TOPMed (Bravo)	AF: 0.651	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.685	AC:263008	Hom:109300	AN:384154	Cov:
Local & regional cohorts 8 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.680	AC:1302	Hom:353	AN:1914	Cov:
Denmark Genome	AF: 0.697	AC:161	Hom:	AN:231	Cov:
ESP6500 (Exome Variant Server)	AF: 0.673	AC:7111	Hom:	AN:10563	Cov:
Korea4K (4,157 Koreans)	AF: 0.437	AC:2278	Hom:	AN:5217	Cov:
Qatari Genome	AF: 0.696	AC:812	Hom:	AN:1166	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.408	AC:41676	Hom:6879	AN:102072	Cov:
Turkish Variome	AF: 0.675	AC:4403	Hom:1826	AN:6526	Cov:
UK10K	AF: 0.704	AC:4642	Hom:	AN:6597	Cov:

Showing 14 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.691 *	4746	6867	0.685 *	8350	12187
BipEx(Bipolar disorder (including schizoaffective))	0.700	19885	28418	0.697	20108	28844
Epi25(Epilepsy)	0.659	27669	41958	0.682	45626	66884
SCHEMA(Schizophrenia)	0.601	54080	90005	0.610	92809	152074

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
-	-	4	not specified (4)
-	-	2	Brunner syndrome (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	7.2
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.9
DANN	Benign	0.48
GPN-Star LLR	N/A	5.8
GPN-Star score	N/A	1.8
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	0.14

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: rs1137070;

hg19: chrX-43603391;

COSMIC: COSV58641635;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar