X-51895557-T-C

Variant names:

• chrX-51895557-T-C
• rs1218543591
• NM_006986.4:c.550T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006986.4(MAGED1):​c.550T>C​(p.Trp184Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,949 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: MAGED1 NM_006986.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.92

Genes affected

MAGED1 (HGNC:6813): (MAGE family member D1) This gene is a member of the melanoma antigen gene (MAGE) family. Most of the genes of this family encode tumor specific antigens that are not expressed in normal adult tissues except testis. Although the protein encoded by this gene shares strong homology with members of the MAGE family, it is expressed in almost all normal adult tissues. This gene has been demonstrated to be involved in the p75 neurotrophin receptor mediated programmed cell death pathway. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGED1	NM_006986.4	c.550T>C	p.Trp184Arg	missense_variant	Exon 3 of 13	ENST00000326587.12	NP_008917.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGED1	ENST00000326587.12	c.550T>C	p.Trp184Arg	missense_variant	Exon 3 of 13	1	NM_006986.4	ENSP00000325333.8

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000548 AC: 1 AN: 182510 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 66974

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097949 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363313

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.718T>C (p.W240R) alteration is located in exon 4 (coding exon 3) of the MAGED1 gene. This alteration results from a T to C substitution at nucleotide position 718, causing the tryptophan (W) at amino acid position 240 to be replaced by an arginine (R). 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	Pathogenic	0.68
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T;T;.
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.69	.;.;T;T
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.61	D;D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.4	L;L;L;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Benign	0.85	T;T;T;T
Polyphen		1.0	D;D;D;D
Vest4		0.57
MutPred		0.42		Loss of catalytic residue at A183 (P = 0.0526);Loss of catalytic residue at A183 (P = 0.0526);Loss of catalytic residue at A183 (P = 0.0526);.;
MVP		0.61
MPC		0.14
ClinPred		0.35	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.71

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: rs1218543591; hg19: chrX-51638653;