X-75784037-C-T

Variant names:

• chrX-75784037-C-T
• rs760592706
• NM_138703.5:c.1015G>A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_138703.5(MAGEE2):​c.1015G>A​(p.Ala339Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,095,407 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 2 hem.)
• Consequence: MAGEE2 NM_138703.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.33

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]

LOC107985664 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3153007).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEE2	NM_138703.5	c.1015G>A	p.Ala339Thr	missense_variant	Exon 1 of 1	ENST00000373359.4	NP_619648.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGEE2	ENST00000373359.4	c.1015G>A	p.Ala339Thr	missense_variant	Exon 1 of 1	6	NM_138703.5	ENSP00000362457.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000553 AC: 1 AN: 180755 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 66129

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1095407 Hom.: 0 Cov.: 31 AF XY: 0.00000553 AC XY: 2 AN XY: 361945

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: 0.00000356

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1015G>A (p.A339T) alteration is located in exon 1 (coding exon 1) of the MAGEE2 gene. This alteration results from a G to A substitution at nucleotide position 1015, causing the alanine (A) at amino acid position 339 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0054	T
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.035	N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.095
Sift	Benign	0.064	T
Sift4G	Benign	0.16	T
Polyphen		1.0	D
Vest4		0.28
MutPred		0.42		Loss of stability (P = 0.0533);
MVP		0.48
MPC		0.083
ClinPred		0.68	D
GERP RS		2.8
Varity_R		0.10
gMVP		0.11

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

Publications

LitVar

Other links and lift over

dbSNP: rs760592706; hg19: chrX-75003872;