X-30250883-G-C

Variant names:

• chrX-30250883-G-C
• rs1925492719
• NM_177404.3:c.390G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_177404.3(MAGEB1):​c.390G>C​(p.Met130Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000886 in 112,838 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
• Consequence: MAGEB1 NM_177404.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.93
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07603219).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEB1	NM_177404.3	c.390G>C	p.Met130Ile	missense_variant	Exon 2 of 2	ENST00000397548.4	NP_796379.1
MAGEB1	NM_002363.5	c.390G>C	p.Met130Ile	missense_variant	Exon 4 of 4		NP_002354.2
MAGEB1	NM_177415.3	c.390G>C	p.Met130Ile	missense_variant	Exon 3 of 3		NP_803134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGEB1	ENST00000397548.4	c.390G>C	p.Met130Ile	missense_variant	Exon 2 of 2	1	NM_177404.3	ENSP00000380681.2
MAGEB1	ENST00000378981.8	c.390G>C	p.Met130Ile	missense_variant	Exon 4 of 4	1		ENSP00000368264.3
MAGEB1	ENST00000397550.6	c.390G>C	p.Met130Ile	missense_variant	Exon 3 of 3	1		ENSP00000380683.1

Frequencies

GnomAD3 genomes AF: 0.00000886 AC: 1 AN: 112838 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000930

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

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000886 AC: 1 AN: 112838 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34990

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31064

American (AMR) AF: 0.0000930 AC: 1 AN: 10748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2662

East Asian (EAS) AF: 0.00 AC: 0 AN: 3588

South Asian (SAS) AF: 0.00 AC: 0 AN: 2692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6277

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53356

Other (OTH) AF: 0.00 AC: 0 AN: 1527

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 24, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.390G>C (p.M130I) alteration is located in exon 4 (coding exon 1) of the MAGEB1 gene. This alteration results from a G to C substitution at nucleotide position 390, causing the methionine (M) at amino acid position 130 to be replaced by an isoleucine (I). 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	-0.61	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.038
DANN	Benign	0.80
DEOGEN2	Benign	0.017	T;T;T
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.21	.;T;.
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.076	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L;L;L
PhyloP100		-2.9
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.93	N;N;N
REVEL	Benign	0.0080
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.051
MutPred		0.48		Gain of methylation at K131 (P = 0.0779);Gain of methylation at K131 (P = 0.0779);Gain of methylation at K131 (P = 0.0779);
MVP		0.20
MPC		0.054
ClinPred		0.11	T
GERP RS		-8.0
Varity_R		0.16
gMVP		0.24
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1925492719; hg19: chrX-30269000;