X-51895203-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006986.4(MAGED1):c.196C>G(p.Gln66Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,097,853 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 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: 0.000016 (0 hom. 6 hem.)
• Consequence: MAGED1 NM_006986.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.939

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031101465).
• BS2: High Hemizygotes in GnomAdExome at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAGED1	NM_006986.4	c.196C>G	p.Gln66Glu	missense_variant	3/13	ENST00000326587.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAGED1	ENST00000326587.12	c.196C>G	p.Gln66Glu	missense_variant	3/13	1	NM_006986.4	P2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000876 AC: 16 AN: 182574 Hom.: 0 AF XY: 0.0000745 AC XY: 5 AN XY: 67080

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000585

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 18 AN: 1097853 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 6 AN XY: 363227

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000426

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

Bravo AF: 0.0000189

ExAC AF: 0.0000824 AC: 10

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

Jan 09, 2023

The c.364C>G (p.Q122E) alteration is located in exon 4 (coding exon 3) of the MAGED1 gene. This alteration results from a C to G substitution at nucleotide position 364, causing the glutamine (Q) at amino acid position 122 to be replaced by a glutamic acid (E). 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	0.069
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.95
Cadd	Benign	16
Dann	Benign	0.80
DEOGEN2	Benign	0.15	T;T;T;.
FATHMM_MKL	Benign	0.36	N
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.031	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.75	N;N;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.54	N;N;N;N
REVEL	Benign	0.033
Sift	Benign	0.59	T;T;T;T
Sift4G	Benign	0.47	T;T;T;T
Polyphen		0.073	B;B;B;B
Vest4		0.12
MutPred		0.21		Loss of MoRF binding (P = 0.0498);Loss of MoRF binding (P = 0.0498);Loss of MoRF binding (P = 0.0498);.;
MVP		0.36
MPC		0.083
ClinPred		0.011	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.056
gMVP		0.22

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: rs782161142; hg19: chrX-51638299; COSMIC: COSV58516397; COSMIC: COSV58516397;