X-77830846-C-T

Variant names:

• chrX-77830846-C-T
• rs2076895504
• NM_001367916.1:c.951G>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.951G>A​(p.Met317Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000954 in 1,048,026 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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M317V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.5e-7 (0 hom. 0 hem.)
• Consequence: MAGT1 NM_001367916.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.11
• 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=0.35089415).

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.951G>A	p.Met317Ile	missense	Exon 9 of 10	NP_001354845.1	Q9H0U3-1
	MAGT1	NM_032121.5		c.1047G>A	p.Met349Ile	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.951G>A	p.Met317Ile	missense	Exon 9 of 10	ENSP00000480732.1	Q9H0U3-1
	MAGT1	ENST00000358075.11	TSL:1	c.951G>A	p.Met317Ile	missense	Exon 9 of 10	ENSP00000354649.6	Q9H0U3-1
	MAGT1	ENST00000688650.1		c.861G>A	p.Met287Ile	missense	Exon 8 of 9	ENSP00000509785.1	A0A8I5KYH1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.54e-7 AC: 1 AN: 1048026 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 329702

⚠️ 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: 25021

American (AMR) AF: 0.00 AC: 0 AN: 33144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18170

East Asian (EAS) AF: 0.00 AC: 0 AN: 28309

South Asian (SAS) AF: 0.00 AC: 0 AN: 47906

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3925

European-Non Finnish (NFE) AF: 0.00000124 AC: 1 AN: 809344

Other (OTH) AF: 0.00 AC: 0 AN: 43567

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.089	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.97	N
PhyloP100		4.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.21
Sift	Benign	0.20	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.47
MutPred		0.59		Gain of MoRF binding (P = 0.1836)
MVP		0.52
MPC		0.52
ClinPred		0.49	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.89
Mutation Taster		=79/21	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

dbSNP: rs2076895504; hg19: chrX-77086343; COSMIC: COSV100800263;