X-30250620-C-T

Variant names:

• chrX-30250620-C-T
• NM_177404.3:c.127C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_177404.3(MAGEB1):​c.127C>T​(p.Pro43Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,095,308 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: MAGEB1 NM_177404.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.81
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04275784).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEB1	NM_177404.3	c.127C>T	p.Pro43Ser	missense_variant	Exon 2 of 2	ENST00000397548.4	NP_796379.1
MAGEB1	NM_002363.5	c.127C>T	p.Pro43Ser	missense_variant	Exon 4 of 4		NP_002354.2
MAGEB1	NM_177415.3	c.127C>T	p.Pro43Ser	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.127C>T	p.Pro43Ser	missense_variant	Exon 2 of 2	1	NM_177404.3	ENSP00000380681.2
MAGEB1	ENST00000378981.8	c.127C>T	p.Pro43Ser	missense_variant	Exon 4 of 4	1		ENSP00000368264.3
MAGEB1	ENST00000397550.6	c.127C>T	p.Pro43Ser	missense_variant	Exon 3 of 3	1		ENSP00000380683.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1095308 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 1 AN XY: 360866

⚠️ 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: 26307

American (AMR) AF: 0.00 AC: 0 AN: 35043

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19338

East Asian (EAS) AF: 0.00 AC: 0 AN: 30064

South Asian (SAS) AF: 0.00 AC: 0 AN: 53441

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4127

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840643

Other (OTH) AF: 0.0000435 AC: 2 AN: 45983

⚠️ 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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.127C>T (p.P43S) alteration is located in exon 4 (coding exon 1) of the MAGEB1 gene. This alteration results from a C to T substitution at nucleotide position 127, causing the proline (P) at amino acid position 43 to be replaced by a serine (S). 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	Benign	0.075
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.17
DANN	Benign	0.35
DEOGEN2	Benign	0.017	T;T;T
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.21	.;T;.
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.043	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.070	N;N;N
PhyloP100		-1.8
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.042
Sift	Benign	0.57	T;T;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.024	B;B;B
Vest4		0.029
MutPred		0.16		Gain of glycosylation at P43 (P = 0.0105);Gain of glycosylation at P43 (P = 0.0105);Gain of glycosylation at P43 (P = 0.0105);
MVP		0.20
MPC		0.054
ClinPred		0.048	T
GERP RS		-6.1
Varity_R		0.029
gMVP		0.12
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

hg19: chrX-30268737;