X-30236357-C-T

Variant names:

• chrX-30236357-C-T
• rs768698062
• NM_002365.5:c.433C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002365.5(MAGEB3):​c.433C>T​(p.His145Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MAGEB3 NM_002365.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.572

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.071953446).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEB3	NM_002365.5	c.433C>T	p.His145Tyr	missense_variant	Exon 5 of 5	ENST00000361644.4	NP_002356.2
MAGEB3	NM_001386865.1	c.433C>T	p.His145Tyr	missense_variant	Exon 3 of 3		NP_001373794.1
MAGEB3	XM_011545513.3	c.433C>T	p.His145Tyr	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.433C>T	p.His145Tyr	missense_variant	Exon 5 of 5	2	NM_002365.5	ENSP00000355198.2
MAGEB3	ENST00000620842.1	c.433C>T	p.His145Tyr	missense_variant	Exon 1 of 1	6		ENSP00000478513.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000556 AC: 1 AN: 179861 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 64743

Gnomad AFR exome AF: 0.0000770

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Dec 30, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0020
DANN	Benign	0.20
DEOGEN2	Benign	0.017	T;T
FATHMM_MKL	Benign	0.00091	N
LIST_S2	Benign	0.15	.;T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.072	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.2	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	2.6	N;.
REVEL	Benign	0.074
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.12
MutPred		0.66		Loss of methylation at K143 (P = 0.0703);Loss of methylation at K143 (P = 0.0703);
MVP		0.043
MPC		0.14
ClinPred		0.011	T
GERP RS		-6.1
Varity_R		0.037
gMVP		0.24

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: rs768698062; hg19: chrX-30254474;