Genetic Variant MAGIX:p.Arg206Cys (chrX-49165298-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_024859.4(MAGIX):c.616C>T(p.Arg206Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,180,852 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 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. R206H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000080 ( 0 hom., 4 hem., cov: 24)

Exomes 𝑓: 0.000020 ( 0 hom. 5 hem. )

Consequence

MAGIX
NM_024859.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.00

Variant links:

Genes affected

MAGIX (HGNC:30006): (MAGI family member, X-linked)

MAGIX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26924768).

BS2

High Hemizygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGIX	NM_024859.4 link	c.616C>T	p.Arg206Cys	missense_variant	Exon 5 of 6	ENST00000595224.6	NP_079135.3	Q9H6Y5-1
MAGIX	NM_001395401.1 link	c.439C>T	p.Arg147Cys	missense_variant	Exon 4 of 5		NP_001382330.1
MAGIX	NM_001099681.2 link	c.388C>T	p.Arg130Cys	missense_variant	Exon 4 of 5		NP_001093151.2	Q9H6Y5A0A087WUY6
MAGIX	NM_001099682.2 link	c.388C>T	p.Arg130Cys	missense_variant	Exon 4 of 5		NP_001093152.2	Q9H6Y5A0A087X263

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGIX	ENST00000595224.6 link	c.616C>T	p.Arg206Cys	missense_variant	Exon 5 of 6	5	NM_024859.4	ENSP00000471299.1		Q9H6Y5-1

Frequencies

GnomAD3 genomes

AF:

0.0000802

AC:

AN:

112288

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

34460

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000941

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000752

Gnomad OTH

AF:

0.00199

GnomAD3 exomes

AF:

0.00000763

AC:

AN:

131041

Hom.:

AF XY:

0.00

AC XY:

AN XY:

40197

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000102

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000197

AC:

AN:

1068564

Hom.:

Cov.:

AF XY:

0.0000144

AC XY:

AN XY:

346594

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000330

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000353

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000169

Gnomad4 OTH exome

AF:

0.000111

GnomAD4 genome

AF:

0.0000802

AC:

AN:

112288

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

34460

show subpopulations

Gnomad4 AFR

AF:

0.0000324

Gnomad4 AMR

AF:

0.0000941

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000752

Gnomad4 OTH

AF:

0.00199

Bravo

AF:

0.000121

ExAC

AF:

0.0000342

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.616C>T (p.R206C) alteration is located in exon 5 (coding exon 5) of the MAGIX gene. This alteration results from a C to T substitution at nucleotide position 616, causing the arginine (R) at amino acid position 206 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.91

DANN

Benign

0.94

DEOGEN2

Benign

0.087

.;T;T;T;T;T

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.74

T;T;T;T;T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.27

T;T;T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Pathogenic

3.0

.;.;.;M;.;.

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-3.9

.;.;.;.;.;D

REVEL

Benign

0.096

Sift

Uncertain

0.0010

.;.;.;.;.;D

Sift4G

Uncertain

0.022

D;D;D;D;D;D

Polyphen

0.025

B;.;.;B;.;B

Vest4

0.076

MutPred

0.54

.;.;.;Loss of MoRF binding (P = 0.0031);.;.;

MVP

0.20

ClinPred

0.48

GERP RS

-4.1

Varity_R

0.11

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over