X-77830893-T-C

Position:

• chrX-77830893-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001367916.1(MAGT1):​c.904A>G​(p.Met302Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000143 in 980,714 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000014 (0 hom. 3 hem.)
• Consequence: MAGT1 NM_001367916.1 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.15

Genes affected

MAGT1 (HGNC:28880): (magnesium transporter 1) This gene encodes a ubiquitously expressed magnesium cation transporter protein that localizes to the cell membrane. This protein also associates with N-oligosaccharyl transferase and therefore may have a role in N-glycosylation. Mutations in this gene cause a form of X-linked intellectual disability (XLID). This gene may have multiple in-frame translation initiation sites, one of which would encode a shorter protein with an N-terminus containing a signal peptide at amino acids 1-29. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGT1	NM_001367916.1	c.904A>G	p.Met302Val	missense_variant, splice_region_variant	9/10	ENST00000618282.5	NP_001354845.1
MAGT1	NM_032121.5	c.1000A>G	p.Met334Val	missense_variant, splice_region_variant	9/10		NP_115497.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGT1	ENST00000618282.5	c.904A>G	p.Met302Val	missense_variant, splice_region_variant	9/10	1	NM_001367916.1	ENSP00000480732	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000143 AC: 14 AN: 980714 Hom.: 0 Cov.: 19 AF XY: 0.0000104 AC XY: 3 AN XY: 287694

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: 0.0000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 24, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with MAGT1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 334 of the MAGT1 protein (p.Met334Val). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 25, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T;T;T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.7	.;.;L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.0	N;.;.
REVEL	Uncertain	0.37
Sift	Benign	0.10	T;.;.
Sift4G	Benign	0.22	T;T;T
Polyphen		0.0050	.;.;B
Vest4		0.63
MVP		0.93
MPC		0.48
ClinPred		0.67	D
GERP RS		5.5
Varity_R		0.57
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs890032923; hg19: chrX-77086390; COSMIC: COSV63780896;