X-30236842-G-T

Position:

• chrX-30236842-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002365.5(MAGEB3):​c.918G>T​(p.Trp306Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00978 in 1,210,394 control chromosomes in the GnomAD database, including 54 homozygotes. There are 3,921 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (1 hom., 239 hem., cov: 24)
  • Exomes 𝑓: 0.010 (53 hom. 3682 hem.)
• Consequence: MAGEB3 NM_002365.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0640

Genes affected

MAGEB3 (HGNC:6810): (MAGE family member B3) This gene is a MAGE-B subfamily member of the MAGE gene family. MAGE family member proteins direct the expression of tumor antigens recognized on a human melanoma by autologous cytolytic T lymphocytes. There are two known clusters of MAGE genes on chromosome X. The members of the MAGE-A subfamily are located in the Xq28 region, while the members of the MAGE-B subfamily are clustered in the Xp21 region. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011428148).
• BP6: Variant X-30236842-G-T is Benign according to our data. Variant chrX-30236842-G-T is described in ClinVar as [Benign]. Clinvar id is 777315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 239 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGEB3	NM_002365.5	c.918G>T	p.Trp306Cys	missense_variant	5/5	ENST00000361644.4	NP_002356.2
MAGEB3	NM_001386865.1	c.918G>T	p.Trp306Cys	missense_variant	3/3		NP_001373794.1
MAGEB3	XM_011545513.3	c.918G>T	p.Trp306Cys	missense_variant	4/4		XP_011543815.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGEB3	ENST00000361644.4	c.918G>T	p.Trp306Cys	missense_variant	5/5	2	NM_002365.5	ENSP00000355198	P1
MAGEB3	ENST00000620842.1	c.918G>T	p.Trp306Cys	missense_variant	1/1			ENSP00000478513	P1

Frequencies

GnomAD3 genomes AF: 0.00739 AC: 829 AN: 112231 Hom.: 1 Cov.: 24 AF XY: 0.00695 AC XY: 239 AN XY: 34383

Gnomad AFR AF: 0.00156

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00132

Gnomad ASJ AF: 0.00226

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000747

Gnomad FIN AF: 0.0139

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.00661

GnomAD3 exomes AF: 0.00749 AC: 1374 AN: 183472 Hom.: 6 AF XY: 0.00758 AC XY: 515 AN XY: 67906

Gnomad AFR exome AF: 0.00167

Gnomad AMR exome AF: 0.00109

Gnomad ASJ exome AF: 0.000801

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00178

Gnomad FIN exome AF: 0.0142

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.00971

GnomAD4 exome AF: 0.0100 AC: 11011 AN: 1098111 Hom.: 53 Cov.: 32 AF XY: 0.0101 AC XY: 3682 AN XY: 363469

Gnomad4 AFR exome AF: 0.000985

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00144

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.00146

Gnomad4 FIN exome AF: 0.0173

Gnomad4 NFE exome AF: 0.0115

Gnomad4 OTH exome AF: 0.00881

GnomAD4 genome AF: 0.00738 AC: 829 AN: 112283 Hom.: 1 Cov.: 24 AF XY: 0.00694 AC XY: 239 AN XY: 34445

Gnomad4 AFR AF: 0.00155

Gnomad4 AMR AF: 0.00132

Gnomad4 ASJ AF: 0.00226

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000749

Gnomad4 FIN AF: 0.0139

Gnomad4 NFE AF: 0.0125

Gnomad4 OTH AF: 0.00653

Alfa AF: 0.0109 Hom.: 494

Bravo AF: 0.00583

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.0111 AC: 32

ESP6500AA AF: 0.00183 AC: 7

ESP6500EA AF: 0.00981 AC: 66

ExAC AF: 0.00838 AC: 1017

EpiCase AF: 0.00823

EpiControl AF: 0.00877

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.1
DANN	Benign	0.29
DEOGEN2	Benign	0.077	T;T
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.24	.;T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.9	N;.
REVEL	Benign	0.047
Sift	Benign	0.22	T;.
Sift4G	Benign	0.20	T;T
Polyphen		0.0010	B;B
Vest4		0.16
MutPred		0.53		Loss of MoRF binding (P = 0.0523);Loss of MoRF binding (P = 0.0523);
MVP		0.12
MPC		0.19
ClinPred		0.0026	T
GERP RS		1.4
Varity_R		0.17
gMVP		0.63

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: rs138581582; hg19: chrX-30254959;