X-30250540-G-T

Variant names:

• chrX-30250540-G-T
• rs200931248
• NM_177404.3:c.47G>T

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.47G>T​(p.Arg16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000917 in 1,090,501 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R16H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: MAGEB1 NM_177404.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00800
• 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=0.24045071).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEB1	NM_177404.3	c.47G>T	p.Arg16Leu	missense_variant	Exon 2 of 2	ENST00000397548.4	NP_796379.1
MAGEB1	NM_002363.5	c.47G>T	p.Arg16Leu	missense_variant	Exon 4 of 4		NP_002354.2
MAGEB1	NM_177415.3	c.47G>T	p.Arg16Leu	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.47G>T	p.Arg16Leu	missense_variant	Exon 2 of 2	1	NM_177404.3	ENSP00000380681.2
MAGEB1	ENST00000378981.8	c.47G>T	p.Arg16Leu	missense_variant	Exon 4 of 4	1		ENSP00000368264.3
MAGEB1	ENST00000397550.6	c.47G>T	p.Arg16Leu	missense_variant	Exon 3 of 3	1		ENSP00000380683.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.17e-7 AC: 1 AN: 1090501 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 356955

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

African (AFR) AF: 0.00 AC: 0 AN: 26116

American (AMR) AF: 0.00 AC: 0 AN: 34084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19004

East Asian (EAS) AF: 0.00 AC: 0 AN: 30059

South Asian (SAS) AF: 0.00 AC: 0 AN: 52363

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4087

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 838725

Other (OTH) AF: 0.00 AC: 0 AN: 45761

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T;T;T
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.43	.;T;.
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L;L
PhyloP100		0.0080
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Benign	0.038
Sift	Uncertain	0.013	D;D;D
Sift4G	Benign	0.089	T;T;T
Polyphen		0.99	D;D;D
Vest4		0.31
MutPred		0.30		Loss of methylation at K17 (P = 0.0496);Loss of methylation at K17 (P = 0.0496);Loss of methylation at K17 (P = 0.0496);
MVP		0.56
MPC		0.35
ClinPred		0.96	D
GERP RS		0.22
Varity_R		0.31
gMVP		0.14
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: rs200931248; hg19: chrX-30268657;