chrX-151923960-C-G

Variant names:

• chrX-151923960-C-G
• rs200774631
• NM_001011548.1:c.296C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001011548.1(MAGEA4):​c.296C>G​(p.Ser99Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000909 in 1,210,012 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S99L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000082 (0 hom. 1 hem.)
• Consequence: MAGEA4 NM_001011548.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.75
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07481772).

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.296C>G	p.Ser99Trp	missense	Exon 3 of 3	NP_001011548.1	P43358
	MAGEA4	NM_001011549.1		c.296C>G	p.Ser99Trp	missense	Exon 3 of 3	NP_001011549.1	P43358
	MAGEA4	NM_001011550.1		c.296C>G	p.Ser99Trp	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.296C>G	p.Ser99Trp	missense	Exon 3 of 3	ENSP00000276344.2	P43358
	MAGEA4	ENST00000360243.6	TSL:1	c.296C>G	p.Ser99Trp	missense	Exon 3 of 3	ENSP00000353379.2	P43358
	MAGEA4	ENST00000370335.5	TSL:1	c.296C>G	p.Ser99Trp	missense	Exon 3 of 3	ENSP00000359360.1	P43358

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112461 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000646

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 182192 AF XY: 0.0000150

Gnomad AFR exome AF: 0.000152

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000820 AC: 9 AN: 1097498 Hom.: 0 Cov.: 36 AF XY: 0.00000276 AC XY: 1 AN XY: 362928

African (AFR) AF: 0.000189 AC: 5 AN: 26394

American (AMR) AF: 0.0000284 AC: 1 AN: 35169

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19320

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 53987

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40353

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4131

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841872

Other (OTH) AF: 0.0000651 AC: 3 AN: 46067

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112514 Hom.: 0 Cov.: 23 AF XY: 0.0000289 AC XY: 1 AN XY: 34660

African (AFR) AF: 0.0000645 AC: 2 AN: 31023

American (AMR) AF: 0.00 AC: 0 AN: 10717

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3565

South Asian (SAS) AF: 0.00 AC: 0 AN: 2682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53241

Other (OTH) AF: 0.00 AC: 0 AN: 1533

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.00000824 AC: 1

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	0.15
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.4
DANN	Benign	0.96
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.00092	T
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		-2.7
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.095
Sift	Uncertain	0.029	D
Sift4G	Benign	0.20	T
Polyphen		1.0	D
Vest4		0.32
MVP		0.18
MPC		0.0035
ClinPred		0.21	T
GERP RS		-4.9
Varity_R		0.060
gMVP		0.15
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: rs200774631; hg19: chrX-151092432;