rs1555947954

Positions:

• chrX-43711965-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001270458.2(MAOA):​c.1A>G​(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 0.00000471 in 1,061,561 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: 0.0000047 (0 hom. 0 hem.)
• Consequence: MAOA NM_001270458.2 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.53

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAOA	NM_000240.4	c.400A>G	p.Met134Val	missense_variant	4/15	ENST00000338702.4	NP_000231.1
MAOA	NM_001270458.2	c.1A>G	p.Met1?	start_lost	5/16		NP_001257387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAOA	ENST00000338702.4	c.400A>G	p.Met134Val	missense_variant	4/15	1	NM_000240.4	ENSP00000340684.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000471 AC: 5 AN: 1061561 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 330121

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000618

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.78	.;D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.4	.;M
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.21	.;B
Vest4		0.68
MutPred		0.67		.;Gain of ubiquitination at K136 (P = 0.0856);
MVP		0.99
MPC		1.2
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.77
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555947954; hg19: chrX-43571212;