X-151924100-C-T

Variant names:

• chrX-151924100-C-T
• rs768575994
• NM_001011548.1:c.436C>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.436C>T​(p.Arg146Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,210,726 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 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 0.000036 (0 hom., 2 hem., cov: 24)
  • Exomes 𝑓: 0.0000091 (0 hom. 2 hem.)
• Consequence: MAGEA4 NM_001011548.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.357

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=0.117432386).
• BS2: High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEA4	NM_001011548.1	c.436C>T	p.Arg146Cys	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.436C>T	p.Arg146Cys	missense_variant	Exon 3 of 3	2	NM_001011548.1	ENSP00000276344.2

Frequencies

GnomAD3 genomes AF: 0.0000355 AC: 4 AN: 112531 Hom.: 0 Cov.: 24 AF XY: 0.0000577 AC XY: 2 AN XY: 34681

Gnomad AFR AF: 0.0000323

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: 0.0000563

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000164 AC: 3 AN: 183448 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67912

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000244

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000911 AC: 10 AN: 1098195 Hom.: 0 Cov.: 37 AF XY: 0.00000550 AC XY: 2 AN XY: 363561

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.00

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: 0.00000950

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000355 AC: 4 AN: 112531 Hom.: 0 Cov.: 24 AF XY: 0.0000577 AC XY: 2 AN XY: 34681

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000563

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.436C>T (p.R146C) 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 436, causing the arginine (R) at amino acid position 146 to be replaced by a cysteine (C). 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	0.11
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.038	T;T;.;T;.;.;T;.;.;.;T;T;T;.
FATHMM_MKL	Benign	0.0056	N
LIST_S2	Benign	0.57	T;T;.;.;.;.;.;T;T;.;.;.;.;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.79	.;N;.;N;.;.;N;.;.;.;N;N;N;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.089
Sift	Uncertain	0.020	D;T;D;T;D;D;T;D;D;D;T;T;T;D
Sift4G	Uncertain	0.019	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;D;.;.;D;.;.;.;D;D;D;.
Vest4		0.25, 0.25
MutPred		0.51		Loss of MoRF binding (P = 0.0011);Loss of MoRF binding (P = 0.0011);Loss of MoRF binding (P = 0.0011);Loss of MoRF binding (P = 0.0011);Loss of MoRF binding (P = 0.0011);Loss of MoRF binding (P = 0.0011);Loss of MoRF binding (P = 0.0011);Loss of MoRF binding (P = 0.0011);Loss of MoRF binding (P = 0.0011);Loss of MoRF binding (P = 0.0011);Loss of MoRF binding (P = 0.0011);Loss of MoRF binding (P = 0.0011);Loss of MoRF binding (P = 0.0011);Loss of MoRF binding (P = 0.0011);
MVP		0.10
MPC		0.0078
ClinPred		0.22	T
GERP RS		-4.3
Varity_R		0.34
gMVP		0.18

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: rs768575994; hg19: chrX-151092572;