X-152767130-T-A

Position:

• chrX-152767130-T-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_005363.5(MAGEA6):​c.521A>T​(p.His174Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,097,282 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000055 (0 hom. 3 hem.)
• Consequence: MAGEA6 NM_005363.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.467

Genes affected

MAGEA6 (HGNC:6804): (MAGE family member A6) 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. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816
• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGEA6	NM_005363.5	c.521A>T	p.His174Leu	missense_variant	3/3	ENST00000329342.10	NP_005354.1
MAGEA6	NM_175868.4	c.521A>T	p.His174Leu	missense_variant	3/3		NP_787064.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGEA6	ENST00000329342.10	c.521A>T	p.His174Leu	missense_variant	3/3	1	NM_005363.5	ENSP00000329199.5
MAGEA6	ENST00000616035.4	c.521A>T	p.His174Leu	missense_variant	3/3	5		ENSP00000480637.1
MAGEA6	ENST00000457643.1	c.521A>T	p.His174Leu	missense_variant	4/4	3		ENSP00000401806.1
MAGEA6	ENST00000412733.1	c.521A>T	p.His174Leu	missense_variant	3/3	5		ENSP00000403303.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000547 AC: 6 AN: 1097282 Hom.: 0 Cov.: 31 AF XY: 0.00000827 AC XY: 3 AN XY: 362642

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2024

The c.521A>T (p.H174L) alteration is located in exon 3 (coding exon 1) of the MAGEA6 gene. This alteration results from a A to T substitution at nucleotide position 521, causing the histidine (H) at amino acid position 174 to be replaced by a leucine (L). 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	0.19
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.85
DEOGEN2	Benign	0.25	T;T;.;T
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.16	.;T;T;T
M_CAP	Benign	0.00072	T
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-10	D;.;D;D
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Pathogenic	0.0010	D;D;.;.
Vest4		0.30
MutPred		0.73		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.36
ClinPred		1.0	D
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.47
gMVP		0.73

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-151935646;