X-75783503-T-C

Variant names:

• chrX-75783503-T-C
• rs369188603
• NM_138703.5:c.1549A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138703.5(MAGEE2):​c.1549A>G​(p.Met517Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000415 in 1,205,811 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M517L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000037 (0 hom. 1 hem.)
• Consequence: MAGEE2 NM_138703.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.996
• Publications: 0 publications found

Genes affected

MAGEE2 (HGNC:24935): (MAGE family member E2) This gene encodes a member of the E subfamily of MAGE (melanoma antigen-encoding gene) gene family. The gene is intronless and the encoded protein has two of the MAGE domains which are characteristic of MAGE family proteins. [provided by RefSeq, Sep 2011]

MAGEE2 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: XL Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center

LOC107985664 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13346338).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138703.5. 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
	MAGEE2	NM_138703.5	MANE Select	c.1549A>G	p.Met517Val	missense	Exon 1 of 1	NP_619648.1	Q8TD90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGEE2	ENST00000373359.4	TSL:6 MANE Select	c.1549A>G	p.Met517Val	missense	Exon 1 of 1	ENSP00000362457.2	Q8TD90

Frequencies

GnomAD3 genomes AF: 0.00000897 AC: 1 AN: 111506 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000366 AC: 4 AN: 1094305 Hom.: 0 Cov.: 30 AF XY: 0.00000278 AC XY: 1 AN XY: 360303

African (AFR) AF: 0.00 AC: 0 AN: 26275

American (AMR) AF: 0.00 AC: 0 AN: 34945

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19244

East Asian (EAS) AF: 0.00 AC: 0 AN: 30102

South Asian (SAS) AF: 0.00 AC: 0 AN: 53863

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4114

European-Non Finnish (NFE) AF: 0.00000477 AC: 4 AN: 839424

Other (OTH) AF: 0.00 AC: 0 AN: 45906

GnomAD4 genome AF: 0.00000897 AC: 1 AN: 111506 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33676

African (AFR) AF: 0.0000326 AC: 1 AN: 30628

American (AMR) AF: 0.00 AC: 0 AN: 10490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3535

South Asian (SAS) AF: 0.00 AC: 0 AN: 2636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53156

Other (OTH) AF: 0.00 AC: 0 AN: 1499

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.0
DANN	Benign	0.49
DEOGEN2	Benign	0.0091	T
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.054
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.055	T
Polyphen		0.0020	B
Vest4		0.19
MutPred		0.42		Loss of helix (P = 0.0068)
MVP		0.34
MPC		0.012
ClinPred		0.078	T
GERP RS		1.9
Varity_R		0.26
gMVP		0.38
Mutation Taster		=98/2	polymorphism

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: rs369188603; hg19: chrX-75003338;