Genetic Variant MAGIX:p.Pro216Ala (chrX-49165328-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_024859.4(MAGIX):c.646C>G(p.Pro216Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,176,518 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 60 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., 5 hem., cov: 23)

Exomes 𝑓: 0.00014 ( 0 hom. 55 hem. )

Consequence

MAGIX
NM_024859.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.09

Variant links:

Genes affected

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

MAGIX links:

ENSG00000279422 (HGNC:):

ENSG00000279422 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030400664).

BS2

High Hemizygotes in GnomAd4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGIX	NM_024859.4 link	c.646C>G	p.Pro216Ala	missense_variant	Exon 5 of 6	ENST00000595224.6	NP_079135.3	Q9H6Y5-1
MAGIX	NM_001395401.1 link	c.469C>G	p.Pro157Ala	missense_variant	Exon 4 of 5		NP_001382330.1
MAGIX	NM_001099681.2 link	c.418C>G	p.Pro140Ala	missense_variant	Exon 4 of 5		NP_001093151.2	Q9H6Y5A0A087WUY6
MAGIX	NM_001099682.2 link	c.418C>G	p.Pro140Ala	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.646C>G	p.Pro216Ala	missense_variant	Exon 5 of 6	5	NM_024859.4	ENSP00000471299.1		Q9H6Y5-1

Frequencies

GnomAD3 genomes

AF:

0.000170

AC:

AN:

111799

Hom.:

Cov.:

AF XY:

0.000147

AC XY:

AN XY:

33971

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000328

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000320

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000122

AC:

AN:

131462

Hom.:

AF XY:

0.0000561

AC XY:

AN XY:

35672

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000469

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000963

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000151

Gnomad NFE exome

AF:

0.000217

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000135

AC:

144

AN:

1064719

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

340659

show subpopulations

Gnomad4 AFR exome

AF:

0.0000391

Gnomad4 AMR exome

AF:

0.0000334

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000694

Gnomad4 SAS exome

AF:

0.0000201

Gnomad4 FIN exome

AF:

0.000129

Gnomad4 NFE exome

AF:

0.000158

Gnomad4 OTH exome

AF:

0.0000894

GnomAD4 genome

AF:

0.000170

AC:

AN:

111799

Hom.:

Cov.:

AF XY:

0.000147

AC XY:

AN XY:

33971

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000328

Gnomad4 NFE

AF:

0.000320

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000291

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.000161

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 01, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.646C>G (p.P216A) alteration is located in exon 5 (coding exon 5) of the MAGIX gene. This alteration results from a C to G substitution at nucleotide position 646, causing the proline (P) at amino acid position 216 to be replaced by an alanine (A). 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

0.073

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.052

DANN

Benign

0.60

DEOGEN2

Benign

0.031

.;T;T;T;T;T

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.68

T;T;T;T;T;T

M_CAP

Benign

0.0041

MetaRNN

Benign

0.030

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

.;.;.;L;.;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.2

.;.;.;.;.;N

REVEL

Benign

0.021

Sift

Benign

0.067

.;.;.;.;.;T

Sift4G

Benign

0.11

T;T;T;T;T;T

Polyphen

0.26

B;.;.;B;.;B

Vest4

0.084

MutPred

0.24

.;.;.;Gain of MoRF binding (P = 0.0311);.;.;

MVP

0.072

ClinPred

0.052

GERP RS

-4.4

Varity_R

0.017

gMVP

0.37

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

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