NM_000240.4:c.3G>A

Variant names:

• chrX-43656344-G-A
• rs1601921232
• NM_000240.4:c.3G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_000240.4(MAOA):​c.3G>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000456 in 1,097,396 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000046 (0 hom. 0 hem.)
• Consequence: MAOA NM_000240.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.57
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 13 codons. Genomic position: 43656378. Lost 0.023 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

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.3G>A	p.Met1?	start_lost	Exon 1 of 15	NP_000231.1	Q53YE7
	MAOA	NM_001270458.2		c.-505G>A		5_prime_UTR	Exon 1 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.3G>A	p.Met1?	start_lost	Exon 1 of 15	ENSP00000340684.3	P21397-1
	MAOA	ENST00000967111.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 15	ENSP00000637170.1
	MAOA	ENST00000873971.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 15	ENSP00000544030.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1097396 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 362796

African (AFR) AF: 0.00 AC: 0 AN: 26387

American (AMR) AF: 0.00 AC: 0 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19380

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.00 AC: 0 AN: 54127

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40407

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000594 AC: 5 AN: 841485

Other (OTH) AF: 0.00 AC: 0 AN: 46070

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Brunner syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-1.1	T
PhyloP100		3.6
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.16
Sift	Benign	0.032	D
Sift4G	Benign	0.11	T
Polyphen		0.14	B
Vest4		0.83
MutPred		0.60		Gain of methylation at K6 (P = 0.1548)
MVP		0.82
ClinPred		0.97	D
GERP RS		4.1
PromoterAI		-0.15	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.94
Mutation Taster		=83/117	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1601921232; hg19: chrX-43515592;