X-152767230-C-T

Position:

• chrX-152767230-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005363.5(MAGEA6):​c.421G>A​(p.Gly141Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,208,516 control chromosomes in the GnomAD database, including 12 homozygotes. There are 1,085 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., 64 hem., cov: 20)
  • Exomes 𝑓: 0.0028 (12 hom. 1021 hem.)
• Consequence: MAGEA6 NM_005363.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -2.54

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03499949).
• BP6: Variant X-152767230-C-T is Benign according to our data. Variant chrX-152767230-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 789367.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 64 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGEA6	NM_005363.5	c.421G>A	p.Gly141Arg	missense_variant	3/3	ENST00000329342.10	NP_005354.1
MAGEA6	NM_175868.4	c.421G>A	p.Gly141Arg	missense_variant	3/3		NP_787064.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGEA6	ENST00000329342.10	c.421G>A	p.Gly141Arg	missense_variant	3/3	1	NM_005363.5	ENSP00000329199.5
MAGEA6	ENST00000616035.4	c.421G>A	p.Gly141Arg	missense_variant	3/3	5		ENSP00000480637.1
MAGEA6	ENST00000457643.1	c.421G>A	p.Gly141Arg	missense_variant	4/4	3		ENSP00000401806.1
MAGEA6	ENST00000412733.1	c.421G>A	p.Gly141Arg	missense_variant	3/3	5		ENSP00000403303.1

Frequencies

GnomAD3 genomes AF: 0.00190 AC: 211 AN: 111231 Hom.: 0 Cov.: 20 AF XY: 0.00191 AC XY: 64 AN XY: 33437

Gnomad AFR AF: 0.000360

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000757

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00153

Gnomad FIN AF: 0.000664

Gnomad MID AF: 0.0294

Gnomad NFE AF: 0.00321

Gnomad OTH AF: 0.00135

GnomAD3 exomes AF: 0.000131 AC: 24 AN: 183043 Hom.: 0 AF XY: 0.000119 AC XY: 8 AN XY: 67485

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

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: 0.000269

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.00283 AC: 3105 AN: 1097236 Hom.: 12 Cov.: 31 AF XY: 0.00282 AC XY: 1021 AN XY: 362598

Gnomad4 AFR exome AF: 0.000493

Gnomad4 AMR exome AF: 0.00117

Gnomad4 ASJ exome AF: 0.00114

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00172

Gnomad4 FIN exome AF: 0.00116

Gnomad4 NFE exome AF: 0.00327

Gnomad4 OTH exome AF: 0.00219

GnomAD4 genome AF: 0.00189 AC: 210 AN: 111280 Hom.: 0 Cov.: 20 AF XY: 0.00191 AC XY: 64 AN XY: 33496

Gnomad4 AFR AF: 0.000359

Gnomad4 AMR AF: 0.00104

Gnomad4 ASJ AF: 0.000757

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00153

Gnomad4 FIN AF: 0.000664

Gnomad4 NFE AF: 0.00321

Gnomad4 OTH AF: 0.00133

Alfa AF: 0.00210 Hom.: 15

Bravo AF: 0.00187

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000298 AC: 2

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000383

EpiControl AF: 0.000298

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 02, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.029
DANN	Benign	0.50
DEOGEN2	Benign	0.0024	T;T;.;T
FATHMM_MKL	Benign	0.0033	N
LIST_S2	Benign	0.38	.;T;T;T
M_CAP	Benign	0.00062	T
MetaRNN	Benign	0.035	T;T;T;T
MetaSVM	Benign	-0.93	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	4.0	N;.;N;N
Sift	Benign	0.41	T;.;T;T
Sift4G	Benign	0.62	T;T;.;.
Vest4		0.048
MutPred		0.52		Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);
MVP		0.42
ClinPred		0.030	T
GERP RS		-2.8
Varity_R		0.035
gMVP		0.20

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: rs145154087; hg19: chrX-151935746; COSMIC: COSV61449175;