X-151924245-A-G

Variant names:

• chrX-151924245-A-G
• rs1933598615
• NM_001011548.1:c.581A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001011548.1(MAGEA4):​c.581A>G​(p.Asn194Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000579 in 1,208,644 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: MAGEA4 NM_001011548.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.29

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

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08170536).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEA4	NM_001011548.1	c.581A>G	p.Asn194Ser	missense_variant	Exon 3 of 3	ENST00000276344.6	NP_001011548.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGEA4	ENST00000276344.6	c.581A>G	p.Asn194Ser	missense_variant	Exon 3 of 3	2	NM_001011548.1	ENSP00000276344.2

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112133 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34283

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000188

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

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1096511 Hom.: 0 Cov.: 33 AF XY: 0.00000553 AC XY: 2 AN XY: 361973

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000142

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112133 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34283

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000188

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.581A>G (p.N194S) alteration is located in exon 3 (coding exon 1) of the MAGEA4 gene. This alteration results from a A to G substitution at nucleotide position 581, causing the asparagine (N) at amino acid position 194 to be replaced by a serine (S). 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	0.085
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.17
DANN	Benign	0.56
DEOGEN2	Benign	0.0067	T;.;T;.;.;T;.;.;.;T;T;T;.
FATHMM_MKL	Benign	0.0061	N
LIST_S2	Benign	0.062	T;.;.;.;.;.;T;T;.;.;.;.;T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.082	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	L;.;L;.;.;L;.;.;.;L;L;L;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.0030
Sift	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.40	B;.;B;.;.;B;.;.;.;B;B;B;.
Vest4		0.027
MutPred		0.30		Gain of ubiquitination at K199 (P = 0.0931);Gain of ubiquitination at K199 (P = 0.0931);Gain of ubiquitination at K199 (P = 0.0931);Gain of ubiquitination at K199 (P = 0.0931);Gain of ubiquitination at K199 (P = 0.0931);Gain of ubiquitination at K199 (P = 0.0931);Gain of ubiquitination at K199 (P = 0.0931);Gain of ubiquitination at K199 (P = 0.0931);Gain of ubiquitination at K199 (P = 0.0931);Gain of ubiquitination at K199 (P = 0.0931);Gain of ubiquitination at K199 (P = 0.0931);Gain of ubiquitination at K199 (P = 0.0931);Gain of ubiquitination at K199 (P = 0.0931);
MVP		0.23
MPC		0.0039
ClinPred		0.084	T
GERP RS		-3.8
Varity_R		0.088
gMVP		0.080

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: rs1933598615; hg19: chrX-151092717;