chrX-30236732-C-A

Variant names:

• chrX-30236732-C-A
• rs139917714
• NM_002365.5:c.808C>A

Variant summary

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

The NM_002365.5(MAGEB3):​c.808C>A​(p.Arg270Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,210,679 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R270H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.000025 (0 hom. 10 hem.)
• Consequence: MAGEB3 NM_002365.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.27

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.057085752).
• BS2: High Hemizygotes in GnomAd4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEB3	NM_002365.5	c.808C>A	p.Arg270Ser	missense_variant	Exon 5 of 5	ENST00000361644.4	NP_002356.2
MAGEB3	NM_001386865.1	c.808C>A	p.Arg270Ser	missense_variant	Exon 3 of 3		NP_001373794.1
MAGEB3	XM_011545513.3	c.808C>A	p.Arg270Ser	missense_variant	Exon 4 of 4		XP_011543815.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGEB3	ENST00000361644.4	c.808C>A	p.Arg270Ser	missense_variant	Exon 5 of 5	2	NM_002365.5	ENSP00000355198.2
MAGEB3	ENST00000620842.1	c.808C>A	p.Arg270Ser	missense_variant	Exon 1 of 1	6		ENSP00000478513.1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 23 AN: 112572 Hom.: 0 Cov.: 23 AF XY: 0.000230 AC XY: 8 AN XY: 34718

Gnomad AFR AF: 0.000710

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000937

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000545 AC: 10 AN: 183465 Hom.: 0 AF XY: 0.0000295 AC XY: 2 AN XY: 67901

Gnomad AFR exome AF: 0.000532

Gnomad AMR exome AF: 0.000109

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000255 AC: 28 AN: 1098107 Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 10 AN XY: 363463

Gnomad4 AFR exome AF: 0.000568

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: 0.00000356

Gnomad4 OTH exome AF: 0.0000651

GnomAD4 genome AF: 0.000204 AC: 23 AN: 112572 Hom.: 0 Cov.: 23 AF XY: 0.000230 AC XY: 8 AN XY: 34718

Gnomad4 AFR AF: 0.000710

Gnomad4 AMR AF: 0.0000937

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000422 Hom.: 0

Bravo AF: 0.000246

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.808C>A (p.R270S) alteration is located in exon 5 (coding exon 1) of the MAGEB3 gene. This alteration results from a C to A substitution at nucleotide position 808, causing the arginine (R) at amino acid position 270 to be replaced by a serine (S). 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	0.20
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.31
DANN	Benign	0.95
DEOGEN2	Benign	0.014	T;T
FATHMM_MKL	Benign	0.0083	N
LIST_S2	Benign	0.21	.;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.057	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.51	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.037
Sift	Benign	0.19	T;.
Sift4G	Benign	0.46	T;T
Polyphen		0.25	B;B
Vest4		0.077
MVP		0.043
MPC		0.26
ClinPred		0.043	T
GERP RS		-3.3
Varity_R		0.24
gMVP		0.51

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: rs139917714; hg19: chrX-30254849;