chrX-77830825-T-G

Position:

• chrX-77830825-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001367916.1(MAGT1):​c.972A>C​(p.Lys324Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: MAGT1 NM_001367916.1 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.46

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_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant X-77830825-T-G is Pathogenic according to our data. Variant chrX-77830825-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 625836.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGT1	NM_001367916.1	c.972A>C	p.Lys324Asn	missense_variant	9/10	ENST00000618282.5	NP_001354845.1
MAGT1	NM_032121.5	c.1068A>C	p.Lys356Asn	missense_variant	9/10		NP_115497.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGT1	ENST00000618282.5	c.972A>C	p.Lys324Asn	missense_variant	9/10	1	NM_001367916.1	ENSP00000480732	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 20

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital disorder of glycosylation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing;research

Center for Human Genetics, University of Leuven

Jul 01, 2018

Functional assays were performed to assess the functionality of the protein -

Congenital disorder of glycosylation, type ICC Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T;T
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Pathogenic	3.0	.;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.8	D;.;.
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.17	.;.;B
Vest4		0.89
MutPred		0.86		.;.;Loss of methylation at K324 (P = 0.0011);
MVP		0.94
MPC		0.89
ClinPred		0.99	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		1.0

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: rs373260156; hg19: chrX-77086322;