Genetic Variant MAGIX:p.Pro285Arg (chrX-49166248-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_024859.4(MAGIX):c.854C>G(p.Pro285Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000833 in 1,200,812 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000074 ( 0 hom. 2 hem. )

Consequence

MAGIX
NM_024859.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.359

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08831784).

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGIX	NM_024859.4 link	c.854C>G	p.Pro285Arg	missense_variant	Exon 6 of 6	ENST00000595224.6	NP_079135.3	Q9H6Y5-1
MAGIX	NM_001395401.1 link	c.677C>G	p.Pro226Arg	missense_variant	Exon 5 of 5		NP_001382330.1
MAGIX	NM_001099681.2 link	c.626C>G	p.Pro209Arg	missense_variant	Exon 5 of 5		NP_001093151.2	Q9H6Y5A0A087WUY6
MAGIX	NM_001099682.2 link	c.611C>G	p.Pro204Arg	missense_variant	Exon 5 of 5		NP_001093152.2	Q9H6Y5A0A087X263

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGIX	ENST00000595224.6 link	c.854C>G	p.Pro285Arg	missense_variant	Exon 6 of 6	5	NM_024859.4	ENSP00000471299.1		Q9H6Y5-1

Frequencies

GnomAD3 genomes

AF:

0.00000886

AC:

AN:

112815

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34957

show subpopulations

Gnomad AFR

AF:

0.0000322

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000735

AC:

AN:

1087945

Hom.:

Cov.:

AF XY:

0.00000563

AC XY:

AN XY:

355555

show subpopulations

Gnomad4 AFR exome

AF:

0.0000764

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000131

GnomAD4 genome

AF:

0.0000177

AC:

AN:

112867

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35019

show subpopulations

Gnomad4 AFR

AF:

0.0000642

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.854C>G (p.P285R) alteration is located in exon 6 (coding exon 6) of the MAGIX gene. This alteration results from a C to G substitution at nucleotide position 854, causing the proline (P) at amino acid position 285 to be replaced by an arginine (R). 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

0.077

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.92

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.030

.;T;T;T;T

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.71

T;T;T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.088

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

.;.;.;L;.

PrimateAI

Benign

0.33

Sift4G

Uncertain

0.058

T;T;T;T;T

Polyphen

0.89

P;.;.;P;.

Vest4

0.035

MutPred

0.16

.;.;.;Loss of catalytic residue at P284 (P = 0.0191);.;

MVP

0.095

ClinPred

0.80

GERP RS

0.48

Varity_R

0.048

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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