ENST00000375695.2:c.74A>C

Variant names:

• chrX-51894655-A-C
• rs781805017
• ENST00000375695.2:c.74A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000375695.2(MAGED1):​c.74A>C​(p.His25Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000652 in 1,074,125 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H25R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., 0 hem., cov: 20)
  • Exomes 𝑓: 0.0000065 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MAGED1 ENST00000375695.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.266
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037259787).

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+306A>C		intron	N/A	NP_008917.3
	MAGED1	NM_001005333.2		c.74A>C	p.His25Pro	missense	Exon 3 of 14	NP_001005333.1	Q9Y5V3-2
	MAGED1	NM_001005332.2		c.45+306A>C		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.74A>C	p.His25Pro	missense	Exon 3 of 14	ENSP00000364847.2	Q9Y5V3-2
	MAGED1	ENST00000326587.12	TSL:1 MANE Select	c.45+306A>C		intron	N/A	ENSP00000325333.8	Q9Y5V3-1
	MAGED1	ENST00000898271.1		c.74A>C	p.His25Pro	missense	Exon 3 of 14	ENSP00000568330.1

Frequencies

GnomAD3 genomes AF: 0.0000207 AC: 2 AN: 96531 Hom.: 0 Cov.: 20

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: 0.0000417

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000652 AC: 7 AN: 1074125 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 346789

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

African (AFR) AF: 0.0000401 AC: 1 AN: 24925

American (AMR) AF: 0.00 AC: 0 AN: 30551

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18925

East Asian (EAS) AF: 0.000102 AC: 3 AN: 29340

South Asian (SAS) AF: 0.00 AC: 0 AN: 50636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40019

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3956

European-Non Finnish (NFE) AF: 0.00000361 AC: 3 AN: 830697

Other (OTH) AF: 0.00 AC: 0 AN: 45076

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000443358), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000207 AC: 2 AN: 96535 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 24259

⚠️ 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: 25660

American (AMR) AF: 0.00 AC: 0 AN: 9010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2426

East Asian (EAS) AF: 0.00 AC: 0 AN: 2994

South Asian (SAS) AF: 0.00 AC: 0 AN: 1914

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 169

European-Non Finnish (NFE) AF: 0.0000417 AC: 2 AN: 47981

Other (OTH) AF: 0.00 AC: 0 AN: 1302

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000983081), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.99
CADD	Benign	6.6
DANN	Benign	0.55
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.94	T
PhyloP100		-0.27
PrimateAI	Benign	0.38	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.078
Sift	Benign	0.13	T
Sift4G	Benign	0.21	T
Polyphen		0.026	B
Vest4		0.22
MutPred		0.16		Gain of glycosylation at H25 (P = 0.0158)
MVP		0.068
MPC		0.12
ClinPred		0.041	T
GERP RS		-3.9
gMVP		0.064
Mutation Taster		=95/5	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: rs781805017; hg19: chrX-51637751;