Genetic Variant MAGEE1:p.Cys125Tyr (chrX-76428304-G-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_020932.3(MAGEE1):c.374G>A(p.Cys125Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00878 in 1,209,800 control chromosomes in the GnomAD database, including 50 homozygotes. There are 3,418 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0068 ( 9 hom., 216 hem., cov: 26)

Exomes 𝑓: 0.0090 ( 41 hom. 3202 hem. )

Consequence

MAGEE1
NM_020932.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.421

Variant links:

Genes affected

MAGEE1 (HGNC:24934): (MAGE family member E1) This gene encodes an alpha-dystrobrevin-associated MAGE (melanoma-associated antigen) protein, which is a member of the MAGE family. The protein contains a nuclear localization signal in the N-terminus, 30 12-amino acid repeats beginning at nt 60 with the consensus sequence ASEGPSTSVLPT, and two MAGE domains in the C-terminus. It may play a signaling role in brain, muscle, and peripheral nerve. This gene is located on X chromosome in a region containing loci linked to cognitive disability. [provided by RefSeq, Mar 2010]

MAGEE1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002328813).

BP6

Variant X-76428304-G-A is Benign according to our data. Variant chrX-76428304-G-A is described in ClinVar as [Benign]. Clinvar id is 790293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-76428304-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEE1	NM_020932.3 link	c.374G>A	p.Cys125Tyr	missense_variant	Exon 1 of 1	ENST00000361470.4	NP_065983.1	Q9HCI5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGEE1	ENST00000361470.4 link	c.374G>A	p.Cys125Tyr	missense_variant	Exon 1 of 1	6	NM_020932.3	ENSP00000354912.2		Q9HCI5

Frequencies

GnomAD3 genomes

AF:

0.00682

AC:

763

AN:

111879

Hom.:

Cov.:

AF XY:

0.00631

AC XY:

216

AN XY:

34233

show subpopulations

Gnomad AFR

AF:

0.00117

Gnomad AMI

AF:

0.119

Gnomad AMR

AF:

0.000929

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0178

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00996

Gnomad OTH

AF:

0.000663

GnomAD3 exomes

AF:

0.00671

AC:

1215

AN:

180939

Hom.:

AF XY:

0.00663

AC XY:

440

AN XY:

66323

show subpopulations

Gnomad AFR exome

AF:

0.00163

Gnomad AMR exome

AF:

0.000585

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000630

Gnomad FIN exome

AF:

0.0239

Gnomad NFE exome

AF:

0.00954

Gnomad OTH exome

AF:

0.00492

GnomAD4 exome

AF:

0.00898

AC:

9858

AN:

1097870

Hom.:

Cov.:

AF XY:

0.00881

AC XY:

3202

AN XY:

363392

show subpopulations

Gnomad4 AFR exome

AF:

0.00117

Gnomad4 AMR exome

AF:

0.000568

Gnomad4 ASJ exome

AF:

0.000310

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000462

Gnomad4 FIN exome

AF:

0.0222

Gnomad4 NFE exome

AF:

0.0102

Gnomad4 OTH exome

AF:

0.00577

GnomAD4 genome

AF:

0.00682

AC:

763

AN:

111930

Hom.:

Cov.:

AF XY:

0.00630

AC XY:

216

AN XY:

34296

show subpopulations

Gnomad4 AFR

AF:

0.00117

Gnomad4 AMR

AF:

0.000928

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0178

Gnomad4 NFE

AF:

0.00997

Gnomad4 OTH

AF:

0.000656

Alfa

AF:

0.00829

Hom.:

347

Bravo

AF:

0.00551

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.0125

AC:

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.00907

AC:

ExAC

AF:

0.00647

AC:

786

EpiCase

AF:

0.00802

EpiControl

AF:

0.00872

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 26, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.98

CADD

Benign

DANN

Benign

0.40

DEOGEN2

Benign

0.0073

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.39

MetaRNN

Benign

0.0023

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.69

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.22

REVEL

Benign

0.0090

Sift

Benign

0.089

Sift4G

Benign

0.13

Polyphen

0.28

Vest4

0.031

MVP

0.043

MPC

0.67

ClinPred

0.0016

GERP RS

-3.9

Varity_R

0.094

gMVP

0.30

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over