NM_001011548.1:c.55C>G

Variant names:

• chrX-151923719-C-G
• rs147367105
• NM_001011548.1:c.55C>G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001011548.1(MAGEA4):​c.55C>G​(p.Gln19Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000274 in 1,209,280 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 110 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.00028 (0 hom. 102 hem.)
• Consequence: MAGEA4 NM_001011548.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.330

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03758794).
• BS2: High Hemizygotes in GnomAd4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEA4	NM_001011548.1	c.55C>G	p.Gln19Glu	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.55C>G	p.Gln19Glu	missense_variant	Exon 3 of 3	2	NM_001011548.1	ENSP00000276344.2

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 25 AN: 111602 Hom.: 0 Cov.: 23 AF XY: 0.000237 AC XY: 8 AN XY: 33804

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000943

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00426

Gnomad NFE AF: 0.000434

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000202 AC: 37 AN: 182805 Hom.: 0 AF XY: 0.000148 AC XY: 10 AN XY: 67389

Gnomad AFR exome AF: 0.0000762

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000344

Gnomad OTH exome AF: 0.000888

GnomAD4 exome AF: 0.000279 AC: 306 AN: 1097626 Hom.: 0 Cov.: 37 AF XY: 0.000281 AC XY: 102 AN XY: 363202

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000199

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: 0.000343

Gnomad4 OTH exome AF: 0.000195

GnomAD4 genome AF: 0.000224 AC: 25 AN: 111654 Hom.: 0 Cov.: 23 AF XY: 0.000236 AC XY: 8 AN XY: 33866

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000942

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000434

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000356 Hom.: 1

Bravo AF: 0.000204

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.55C>G (p.Q19E) alteration is located in exon 3 (coding exon 1) of the MAGEA4 gene. This alteration results from a C to G substitution at nucleotide position 55, causing the glutamine (Q) at amino acid position 19 to be replaced by a glutamic acid (E). 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	0.064
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.2
DANN	Benign	0.93
DEOGEN2	Benign	0.015	T;T;.;T;.;.;T;.;.;.;T;T;T;.
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.70	T;T;.;.;.;.;.;T;T;.;.;.;.;T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.038	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	.;M;.;M;.;.;M;.;.;.;M;M;M;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.026
Sift	Benign	0.058	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.081	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.91	.;P;.;P;.;.;P;.;.;.;P;P;P;.
Vest4		0.18, 0.18, 0.18
MVP		0.093
MPC		0.0039
ClinPred		0.027	T
GERP RS		0.41
Varity_R		0.10
gMVP		0.093

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs147367105; hg19: chrX-151092191;