X-151923882-C-G

Variant names:

• chrX-151923882-C-G
• rs763607469
• NM_001011548.1:c.218C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001011548.1(MAGEA4):​c.218C>G​(p.Pro73Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000331 in 1,209,807 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 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. P73L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: MAGEA4 NM_001011548.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.273
• Publications: 1 publications found

Genes affected

MAGEA4 (HGNC:6802): (MAGE family member A4) This gene is a member of the MAGEA gene family. The members of this family encode proteins with 50 to 80% sequence identity to each other. The promoters and first exons of the MAGEA genes show considerable variability, suggesting that the existence of this gene family enables the same function to be expressed under different transcriptional controls. The MAGEA genes are clustered at chromosomal location Xq28. They have been implicated in some hereditary disorders, such as dyskeratosis congenita. Several variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2020]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08441612).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001011548.1. 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
	MAGEA4	NM_001011548.1	MANE Select	c.218C>G	p.Pro73Arg	missense	Exon 3 of 3	NP_001011548.1	P43358
	MAGEA4	NM_001011549.1		c.218C>G	p.Pro73Arg	missense	Exon 3 of 3	NP_001011549.1	P43358
	MAGEA4	NM_001011550.1		c.218C>G	p.Pro73Arg	missense	Exon 3 of 3	NP_001011550.1	P43358

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGEA4	ENST00000276344.6	TSL:2 MANE Select	c.218C>G	p.Pro73Arg	missense	Exon 3 of 3	ENSP00000276344.2	P43358
	MAGEA4	ENST00000360243.6	TSL:1	c.218C>G	p.Pro73Arg	missense	Exon 3 of 3	ENSP00000353379.2	P43358
	MAGEA4	ENST00000370335.5	TSL:1	c.218C>G	p.Pro73Arg	missense	Exon 3 of 3	ENSP00000359360.1	P43358

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 111772 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000651

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183137 AF XY: 0.0000148

Gnomad AFR exome AF: 0.0000760

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: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097980 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 363414

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

African (AFR) AF: 0.00 AC: 0 AN: 26399

American (AMR) AF: 0.00 AC: 0 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 842102

Other (OTH) AF: 0.00 AC: 0 AN: 46094

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 111827 Hom.: 0 Cov.: 23 AF XY: 0.0000294 AC XY: 1 AN XY: 34013

African (AFR) AF: 0.0000649 AC: 2 AN: 30807

American (AMR) AF: 0.00 AC: 0 AN: 10621

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3522

South Asian (SAS) AF: 0.00 AC: 0 AN: 2618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53083

Other (OTH) AF: 0.00 AC: 0 AN: 1526

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	8.7
DANN	Benign	0.92
DEOGEN2	Benign	0.033	T
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		-0.27
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Benign	0.059
Sift	Benign	0.031	D
Sift4G	Uncertain	0.033	D
Polyphen		0.044	B
Vest4		0.083
MutPred		0.27		Gain of MoRF binding (P = 0.0018)
MVP		0.24
MPC		0.0039
ClinPred		0.086	T
GERP RS		-0.82
Varity_R		0.20
gMVP		0.12
Mutation Taster		=100/0	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: rs763607469; hg19: chrX-151092354;