NM_001367916.1:c.906G>A

Variant names:

• chrX-77830891-C-T
• NM_001367916.1:c.906G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M302V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000010 (0 hom. 0 hem.)
• Consequence: MAGT1 NM_001367916.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.49
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

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

  Inheritance: XL, Unknown Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• intellectual disability, X-linked 95

  Inheritance: XL Classification: LIMITED Submitted by: G2P
• X-linked intellectual disability

  Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35273686).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367916.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGT1	NM_001367916.1	MANE Select	c.906G>A	p.Met302Ile	missense	Exon 9 of 10	NP_001354845.1	Q9H0U3-1
	MAGT1	NM_032121.5		c.1002G>A	p.Met334Ile	missense	Exon 9 of 10	NP_115497.4	Q9H0U3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGT1	ENST00000618282.5	TSL:1 MANE Select	c.906G>A	p.Met302Ile	missense	Exon 9 of 10	ENSP00000480732.1	Q9H0U3-1
	MAGT1	ENST00000358075.11	TSL:1	c.906G>A	p.Met302Ile	missense	Exon 9 of 10	ENSP00000354649.6	Q9H0U3-1
	MAGT1	ENST00000688650.1		c.816G>A	p.Met272Ile	missense	Exon 8 of 9	ENSP00000509785.1	A0A8I5KYH1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000101 AC: 1 AN: 986450 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 291036

African (AFR) AF: 0.00 AC: 0 AN: 23506

American (AMR) AF: 0.00 AC: 0 AN: 31011

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17080

East Asian (EAS) AF: 0.00 AC: 0 AN: 26725

South Asian (SAS) AF: 0.00 AC: 0 AN: 40990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36845

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3730

European-Non Finnish (NFE) AF: 0.00000131 AC: 1 AN: 765767

Other (OTH) AF: 0.00 AC: 0 AN: 40796

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.5
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.21
Sift	Benign	0.28	T
Sift4G	Benign	0.26	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	D
GERP RS		5.5
Varity_R		0.64
gMVP		0.96
Mutation Taster		=62/38	polymorphism

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

Other links and lift over

hg19: chrX-77086388;