X-30218887-A-G

Position:

• chrX-30218887-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002364.5(MAGEB2):​c.307A>G​(p.Thr103Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00435 in 1,207,663 control chromosomes in the GnomAD database, including 101 homozygotes. There are 1,393 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (37 hom., 583 hem., cov: 24)
  • Exomes 𝑓: 0.0028 (64 hom. 810 hem.)
• Consequence: MAGEB2 NM_002364.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.726

Genes affected

MAGEB2 (HGNC:6809): (MAGE family member B2) 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. It is expressed in testis and placenta, and in a significant fraction of tumors of various histological types. The MAGEB genes are clustered on chromosome Xp22-p21. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002213806).
• BP6: Variant X-30218887-A-G is Benign according to our data. Variant chrX-30218887-A-G is described in ClinVar as [Benign]. Clinvar id is 785696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGEB2	NM_002364.5	c.307A>G	p.Thr103Ala	missense_variant	2/2	ENST00000378988.5	NP_002355.2
MAGEB2	XM_011545512.2	c.307A>G	p.Thr103Ala	missense_variant	2/2		XP_011543814.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGEB2	ENST00000378988.5	c.307A>G	p.Thr103Ala	missense_variant	2/2	1	NM_002364.5	ENSP00000368273.4

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2182 AN: 112575 Hom.: 36 Cov.: 24 AF XY: 0.0166 AC XY: 578 AN XY: 34721

Gnomad AFR AF: 0.0634

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000365

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0418

Gnomad NFE AF: 0.000731

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.00625 AC: 1087 AN: 173816 Hom.: 29 AF XY: 0.00376 AC XY: 222 AN XY: 59108

Gnomad AFR exome AF: 0.0660

Gnomad AMR exome AF: 0.00619

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000228

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000812

Gnomad OTH exome AF: 0.00570

GnomAD4 exome AF: 0.00280 AC: 3068 AN: 1095034 Hom.: 64 Cov.: 33 AF XY: 0.00225 AC XY: 810 AN XY: 360712

Gnomad4 AFR exome AF: 0.0729

Gnomad4 AMR exome AF: 0.00709

Gnomad4 ASJ exome AF: 0.0000517

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000262

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000650

Gnomad4 OTH exome AF: 0.00683

GnomAD4 genome AF: 0.0194 AC: 2189 AN: 112629 Hom.: 37 Cov.: 24 AF XY: 0.0168 AC XY: 583 AN XY: 34785

Gnomad4 AFR AF: 0.0635

Gnomad4 AMR AF: 0.0135

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000366

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000731

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.00395 Hom.: 145

Bravo AF: 0.0226

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.0558 AC: 214

ESP6500EA AF: 0.000892 AC: 6

ExAC AF: 0.00679 AC: 824

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 30, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.97	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.15
DANN	Benign	0.54
DEOGEN2	Benign	0.023	T
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	L
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.055
Sift	Benign	0.21	T
Sift4G	Benign	0.45	T
Polyphen		0.75	P
Vest4		0.0040
MVP		0.18
MPC		0.0027
ClinPred		0.024	T
GERP RS		1.4
Varity_R		0.076
gMVP		0.11

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: rs7878409; hg19: chrX-30237004;