ENST00000375695.2:c.91C>T

Variant names:

• chrX-51894672-C-T
• rs1304734768
• ENST00000375695.2:c.91C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000375695.2(MAGED1):​c.91C>T​(p.Pro31Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000509 in 1,177,647 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P31P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000094 (0 hom., 0 hem., cov: 19)
  • Exomes 𝑓: 0.0000047 (0 hom. 3 hem.)
• Consequence: MAGED1 ENST00000375695.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.25
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06499612).
• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000375695.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGED1	NM_006986.4	MANE Select	c.45+323C>T		intron	N/A	NP_008917.3
	MAGED1	NM_001005333.2		c.91C>T	p.Pro31Ser	missense	Exon 3 of 14	NP_001005333.1	Q9Y5V3-2
	MAGED1	NM_001005332.2		c.45+323C>T		intron	N/A	NP_001005332.1	Q9Y5V3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGED1	ENST00000375695.2	TSL:1	c.91C>T	p.Pro31Ser	missense	Exon 3 of 14	ENSP00000364847.2	Q9Y5V3-2
	MAGED1	ENST00000326587.12	TSL:1 MANE Select	c.45+323C>T		intron	N/A	ENSP00000325333.8	Q9Y5V3-1
	MAGED1	ENST00000898271.1		c.91C>T	p.Pro31Ser	missense	Exon 3 of 14	ENSP00000568330.1

Frequencies

GnomAD3 genomes AF: 0.00000942 AC: 1 AN: 106159 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000195

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000617 AC: 1 AN: 161969 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000133

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000467 AC: 5 AN: 1071488 Hom.: 0 Cov.: 32 AF XY: 0.00000867 AC XY: 3 AN XY: 345886

African (AFR) AF: 0.00 AC: 0 AN: 24580

American (AMR) AF: 0.00 AC: 0 AN: 28886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18704

East Asian (EAS) AF: 0.00 AC: 0 AN: 30002

South Asian (SAS) AF: 0.00 AC: 0 AN: 50804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40317

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4024

European-Non Finnish (NFE) AF: 0.00000603 AC: 5 AN: 829222

Other (OTH) AF: 0.00 AC: 0 AN: 44949

GnomAD4 genome AF: 0.00000942 AC: 1 AN: 106159 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 28737

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28937

American (AMR) AF: 0.00 AC: 0 AN: 10075

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2572

East Asian (EAS) AF: 0.00 AC: 0 AN: 3334

South Asian (SAS) AF: 0.00 AC: 0 AN: 2233

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.0000195 AC: 1 AN: 51393

Other (OTH) AF: 0.00 AC: 0 AN: 1409

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.98
CADD	Benign	16
DANN	Benign	0.87
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.98	T
PhyloP100		1.2
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.044
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.95	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.22		Loss of catalytic residue at P30 (P = 0.0193)
MVP		0.068
MPC		0.078
ClinPred		0.17	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.13
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs1304734768; hg19: chrX-51637768;