Genetic Variant NM_001367916.1:c.906G>A (chrX-77830891-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001367916.1(MAGT1):c.906G>A(p.Met302Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000101 in 986,450 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000010 ( 0 hom. 0 hem. )

Consequence

MAGT1
NM_001367916.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.49

Variant links:

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]

MAGT1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35273686).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGT1	NM_001367916.1 link	c.906G>A	p.Met302Ile	missense_variant	Exon 9 of 10	ENST00000618282.5	NP_001354845.1
MAGT1	NM_032121.5 link	c.1002G>A	p.Met334Ile	missense_variant	Exon 9 of 10		NP_115497.4	Q9H0U3A0A087WU53

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGT1	ENST00000618282.5 link	c.906G>A	p.Met302Ile	missense_variant	Exon 9 of 10	1	NM_001367916.1	ENSP00000480732.1		Q9H0U3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000101

AC:

AN:

986450

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

291036

show subpopulations

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:

0.00000131

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 334 of the MAGT1 protein (p.Met334Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MAGT1-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MAGT1 protein function with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.12

T;T;T

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.88

.;D;D

M_CAP

Benign

0.032

MetaRNN

Benign

0.35

T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.2

.;.;L

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.90

N;.;.

REVEL

Benign

0.21

Sift

Benign

0.28

T;.;.

Sift4G

Benign

0.26

T;T;T

Polyphen

0.0010

.;.;B

Vest4

0.35

MutPred

0.58

.;.;Loss of ubiquitination at K298 (P = 0.0596);

MVP

0.57

MPC

0.53

ClinPred

0.78

GERP RS

5.5

Varity_R

0.64

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over