X-151923950-C-T

Variant names:

• chrX-151923950-C-T
• rs755313244
• NM_001011548.1:c.286C>T

Variant summary

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

The NM_001011548.1(MAGEA4):​c.286C>T​(p.Pro96Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,440 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. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P96P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 2 hem.)
• Consequence: MAGEA4 NM_001011548.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.03

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=0.1419566).
• 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.286C>T	p.Pro96Ser	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.286C>T	p.Pro96Ser	missense_variant	Exon 3 of 3	2	NM_001011548.1	ENSP00000276344.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000549 AC: 1 AN: 182256 Hom.: 0 AF XY: 0.0000150 AC XY: 1 AN XY: 66804

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 SAS exome AF: 0.0000534

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097440 Hom.: 0 Cov.: 36 AF XY: 0.00000551 AC XY: 2 AN XY: 362884

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.286C>T (p.P96S) alteration is located in exon 3 (coding exon 1) of the MAGEA4 gene. This alteration results from a C to T substitution at nucleotide position 286, causing the proline (P) at amino acid position 96 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	0.094
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	13
DANN	Uncertain	0.97
DEOGEN2	Benign	0.011	T;T;.;T;.;.;T;.;.;.;T;T;T;.
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.73	T;T;.;.;.;.;.;T;T;.;.;.;.;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	.;M;.;M;.;.;M;.;.;.;M;M;M;.
PrimateAI	Benign	0.22	T
PROVEAN	Pathogenic	-4.5	D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.045
Sift	Uncertain	0.0060	D;T;D;T;D;D;T;D;D;D;T;T;T;D
Sift4G	Benign	0.31	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0	.;D;.;D;.;.;D;.;.;.;D;D;D;.
Vest4		0.029, 0.030
MutPred		0.26		Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);Gain of phosphorylation at P96 (P = 0.0033);
MVP		0.23
MPC		0.012
ClinPred		0.62	D
GERP RS		-3.4
Varity_R		0.11
gMVP		0.095

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: rs755313244; hg19: chrX-151092422;