X-51896650-G-T

Position:

• chrX-51896650-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006986.4(MAGED1):​c.995G>T​(p.Trp332Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: MAGED1 NM_006986.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.28

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3298896).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGED1	NM_006986.4	c.995G>T	p.Trp332Leu	missense_variant	4/13	ENST00000326587.12	NP_008917.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGED1	ENST00000326587.12	c.995G>T	p.Trp332Leu	missense_variant	4/13	1	NM_006986.4	ENSP00000325333	P2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2022

The c.1163G>T (p.W388L) alteration is located in exon 5 (coding exon 4) of the MAGED1 gene. This alteration results from a G to T substitution at nucleotide position 1163, causing the tryptophan (W) at amino acid position 388 to be replaced by a leucine (L). 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	0.31
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T;T;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	.;.;D;D
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.7	L;L;L;.
MutationTaster	Benign	0.63	D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.27	N;N;N;N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Benign	0.46	T;T;T;T
Polyphen		1.0	D;D;D;D
Vest4		0.42
MutPred		0.40		Loss of catalytic residue at P335 (P = 0.0357);Loss of catalytic residue at P335 (P = 0.0357);Loss of catalytic residue at P335 (P = 0.0357);.;
MVP		0.42
MPC		0.14
ClinPred		0.73	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.23

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: rs1928764770; hg19: chrX-51639746;