chrX-77895395-G-A

Variant names:

• chrX-77895395-G-A
• rs140854076
• NM_001367916.1:c.16C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_032121.5(MAGT1):​c.112C>T​(p.Arg38Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,210,302 control chromosomes in the GnomAD database, including 5 homozygotes. There are 1,160 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R38P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., 66 hem., cov: 24)
  • Exomes 𝑓: 0.0027 (5 hom. 1094 hem.)
• Consequence: MAGT1 NM_032121.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.650
• Publications: 2 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: Unknown, XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003437698).
• BP6: Variant X-77895395-G-A is Benign according to our data. Variant chrX-77895395-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96214.
• BS2: High Hemizygotes in GnomAd4 at 66 XL,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032121.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGT1	NM_001367916.1	MANE Select	c.16C>T	p.Arg6Trp	missense	Exon 1 of 10	NP_001354845.1
	MAGT1	NM_032121.5		c.112C>T	p.Arg38Trp	missense	Exon 1 of 10	NP_115497.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGT1	ENST00000618282.5	TSL:1 MANE Select	c.16C>T	p.Arg6Trp	missense	Exon 1 of 10	ENSP00000480732.1
	MAGT1	ENST00000358075.11	TSL:1	c.16C>T	p.Arg6Trp	missense	Exon 1 of 10	ENSP00000354649.6
	MAGT1	ENST00000373336.3	TSL:1	c.16C>T	p.Arg6Trp	missense	Exon 1 of 4	ENSP00000362433.3

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 200 AN: 112325 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000942

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.000820

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.00287

Gnomad OTH AF: 0.00198

GnomAD2 exomes AF: 0.00233 AC: 425 AN: 182634 AF XY: 0.00301

Gnomad AFR exome AF: 0.0000763

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000939

Gnomad NFE exome AF: 0.00279

Gnomad OTH exome AF: 0.000665

GnomAD4 exome AF: 0.00266 AC: 2924 AN: 1097926 Hom.: 5 Cov.: 31 AF XY: 0.00301 AC XY: 1094 AN XY: 363286

African (AFR) AF: 0.000227 AC: 6 AN: 26400

American (AMR) AF: 0.000313 AC: 11 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.000155 AC: 3 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30197

South Asian (SAS) AF: 0.00843 AC: 456 AN: 54076

European-Finnish (FIN) AF: 0.000864 AC: 35 AN: 40527

Middle Eastern (MID) AF: 0.00218 AC: 9 AN: 4137

European-Non Finnish (NFE) AF: 0.00276 AC: 2321 AN: 841929

Other (OTH) AF: 0.00180 AC: 83 AN: 46084

GnomAD4 genome AF: 0.00177 AC: 199 AN: 112376 Hom.: 0 Cov.: 24 AF XY: 0.00191 AC XY: 66 AN XY: 34550

African (AFR) AF: 0.000290 AC: 9 AN: 31020

American (AMR) AF: 0.0000940 AC: 1 AN: 10634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3561

South Asian (SAS) AF: 0.00987 AC: 27 AN: 2736

European-Finnish (FIN) AF: 0.000820 AC: 5 AN: 6095

Middle Eastern (MID) AF: 0.00457 AC: 1 AN: 219

European-Non Finnish (NFE) AF: 0.00287 AC: 153 AN: 53244

Other (OTH) AF: 0.00196 AC: 3 AN: 1532

Alfa AF: 0.00228 Hom.: 107

Bravo AF: 0.00136

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00277 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00283 AC: 19

ExAC AF: 0.00287 AC: 349

EpiCase AF: 0.00284

EpiControl AF: 0.00273

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	not specified (1)
-	-	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	Benign	0.091
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.095	T
FATHMM_MKL	Benign	0.0048	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N
PhyloP100		0.65
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.033
Sift	Benign	0.32	T
Sift4G	Benign	0.066	T
Polyphen		0.0	B
Vest4		0.074
MVP		0.093
MPC		0.49
ClinPred		0.014	T
GERP RS		2.0
PromoterAI		-0.057	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.10
gMVP		0.23
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs140854076; hg19: chrX-77150892;