chrX-30250894-T-C

Position:

• chrX-30250894-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000397548.4(MAGEB1):​c.401T>C​(p.Met134Thr) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: MAGEB1 ENST00000397548.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.81

Genes affected

MAGEB1 (HGNC:6808): (MAGE family member B1) This gene is a member of the MAGEB gene family. The members of this family have their entire coding sequences located in the last exon, and the encoded proteins show 50 to 68% sequence identity to each other. The promoters and first exons of the MAGEB genes show considerable variability, suggesting that the existence of this gene family enables the same function to be expressed under different transcriptional controls. This gene is localized in the DSS (dosage-sensitive sex reversal) critical region, and expressed in testis and in a significant fraction of tumors of various histological types. This gene and other MAGEB members are clustered on chromosome Xp22-p21. Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene, however, the full length nature of some variants has not been defined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGEB1	NM_177404.3	c.401T>C	p.Met134Thr	missense_variant	2/2	ENST00000397548.4	NP_796379.1
MAGEB1	NM_002363.5	c.401T>C	p.Met134Thr	missense_variant	4/4		NP_002354.2
MAGEB1	NM_177415.3	c.401T>C	p.Met134Thr	missense_variant	3/3		NP_803134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGEB1	ENST00000397548.4	c.401T>C	p.Met134Thr	missense_variant	2/2	1	NM_177404.3	ENSP00000380681.2
MAGEB1	ENST00000378981.8	c.401T>C	p.Met134Thr	missense_variant	4/4	1		ENSP00000368264.3
MAGEB1	ENST00000397550.6	c.401T>C	p.Met134Thr	missense_variant	3/3	1		ENSP00000380683.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

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

Apr 06, 2023

The c.401T>C (p.M134T) alteration is located in exon 4 (coding exon 1) of the MAGEB1 gene. This alteration results from a T to C substitution at nucleotide position 401, causing the methionine (M) at amino acid position 134 to be replaced by a threonine (T). 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	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T;T;T
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.71	.;T;.
M_CAP	Benign	0.0087	T
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Benign	-0.97	T
MutationAssessor	Pathogenic	3.9	H;H;H
MutationTaster	Benign	0.85	N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.7	D;D;D
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.65
MutPred		0.87		Gain of phosphorylation at M134 (P = 0.0528);Gain of phosphorylation at M134 (P = 0.0528);Gain of phosphorylation at M134 (P = 0.0528);
MVP		0.52
MPC		0.35
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.92
gMVP		0.65

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-30269011;