X-30251360-G-T

Position:

• chrX-30251360-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_177404.3(MAGEB1):​c.867G>T​(p.Leu289Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000264 in 1,098,255 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000026 (0 hom. 10 hem.)
• Consequence: MAGEB1 NM_177404.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.17

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_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30466396).
• BS2: High Hemizygotes in GnomAdExome4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGEB1	NM_177404.3	c.867G>T	p.Leu289Phe	missense_variant	2/2	ENST00000397548.4	NP_796379.1
MAGEB1	NM_002363.5	c.867G>T	p.Leu289Phe	missense_variant	4/4		NP_002354.2
MAGEB1	NM_177415.3	c.867G>T	p.Leu289Phe	missense_variant	3/3		NP_803134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGEB1	ENST00000397548.4	c.867G>T	p.Leu289Phe	missense_variant	2/2	1	NM_177404.3	ENSP00000380681.2
MAGEB1	ENST00000378981.8	c.867G>T	p.Leu289Phe	missense_variant	4/4	1		ENSP00000368264.3
MAGEB1	ENST00000397550.6	c.867G>T	p.Leu289Phe	missense_variant	3/3	1		ENSP00000380683.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000264 AC: 29 AN: 1098255 Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 10 AN XY: 363609

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000344

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

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

Mar 24, 2023

The c.867G>T (p.L289F) alteration is located in exon 4 (coding exon 1) of the MAGEB1 gene. This alteration results from a G to T substitution at nucleotide position 867, causing the leucine (L) at amino acid position 289 to be replaced by a phenylalanine (F). 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	Uncertain	0.36
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T;T
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.70	.;T;.
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L;L
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Benign	0.087
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.29
MutPred		0.43		Loss of MoRF binding (P = 0.1252);Loss of MoRF binding (P = 0.1252);Loss of MoRF binding (P = 0.1252);
MVP		0.51
MPC		0.21
ClinPred		0.86	D
GERP RS		1.6
Varity_R		0.49
gMVP		0.57

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: rs1294138845; hg19: chrX-30269477;