19-35299590-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002361.4(MAG):c.452C>T(p.Ala151Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0053 in 1,602,818 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0040 ( 3 hom., cov: 28)

Exomes 𝑓: 0.0054 ( 37 hom. )

Consequence

MAG
NM_002361.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 2.35

Publications

12 publications found

Variant links:

Genes affected

MAG (HGNC:6783): (myelin associated glycoprotein) The protein encoded by this gene is a type I membrane protein and member of the immunoglobulin superfamily. It is thought to be involved in the process of myelination. It is a lectin that binds to sialylated glycoconjugates and mediates certain myelin-neuron cell-cell interactions. Three alternatively spliced transcripts encoding different isoforms have been described for this gene. [provided by RefSeq, Nov 2010]

MAG Gene-Disease associations (from GenCC):

complex hereditary spastic paraplegia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hereditary spastic paraplegia 75
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

MAG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009121209).

BP6

Variant 19-35299590-C-T is Benign according to our data. Variant chr19-35299590-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 424686.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00396 (602/152004) while in subpopulation NFE AF = 0.00703 (478/67970). AF 95% confidence interval is 0.00651. There are 3 homozygotes in GnomAd4. There are 265 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAG	NM_002361.4 link	c.452C>T	p.Ala151Val	missense_variant	Exon 5 of 11	ENST00000392213.8	NP_002352.1	P20916-1Q53ES7
MAG	NM_001199216.2 link	c.377C>T	p.Ala126Val	missense_variant	Exon 5 of 11		NP_001186145.1	P20916-3
MAG	NM_080600.3 link	c.452C>T	p.Ala151Val	missense_variant	Exon 5 of 12		NP_542167.1	P20916-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAG	ENST00000392213.8 link	c.452C>T	p.Ala151Val	missense_variant	Exon 5 of 11	1	NM_002361.4	ENSP00000376048.2		P20916-1

Frequencies

GnomAD3 genomes

AF:

0.00396

AC:

602

AN:

151888

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00217

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00703

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00368

AC:

899

AN:

244414

AF XY:

0.00385

show subpopulations

Gnomad AFR exome

AF:

0.00107

Gnomad AMR exome

AF:

0.00192

Gnomad ASJ exome

AF:

0.000609

Gnomad EAS exome

AF:

0.0000547

Gnomad FIN exome

AF:

0.000659

Gnomad NFE exome

AF:

0.00577

Gnomad OTH exome

AF:

0.00536

GnomAD4 exome

AF:

0.00544

AC:

7893

AN:

1450814

Hom.:

Cov.:

AF XY:

0.00555

AC XY:

3990

AN XY:

719514

show subpopulations

African (AFR)

AF:

0.00112

AC:

AN:

33180

American (AMR)

AF:

0.00185

AC:

AN:

44212

Ashkenazi Jewish (ASJ)

AF:

0.000347

AC:

AN:

25902

East Asian (EAS)

AF:

0.00

AC:

AN:

39280

South Asian (SAS)

AF:

0.00513

AC:

437

AN:

85240

European-Finnish (FIN)

AF:

0.00102

AC:

AN:

53192

Middle Eastern (MID)

AF:

0.00490

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00633

AC:

6992

AN:

1104314

Other (OTH)

AF:

0.00425

AC:

254

AN:

59774

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

371

742

1114

1485

1856

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

268

536

804

1072

1340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00396

AC:

602

AN:

152004

Hom.:

Cov.:

AF XY:

0.00357

AC XY:

265

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

41506

American (AMR)

AF:

0.00216

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5070

South Asian (SAS)

AF:

0.00478

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.000754

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00703

AC:

478

AN:

67970

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00465

Hom.:

Bravo

AF:

0.00398

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00430

AC:

ExAC

AF:

0.00413

AC:

501

EpiCase

AF:

0.00687

EpiControl

AF:

0.00689

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MAG: BS1 -

Dec 20, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS2 -

Hereditary spastic paraplegia

Uncertain:1

Mar 07, 2017

Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Hereditary spastic paraplegia 75

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

MAG-related disorder

Benign:1

Feb 19, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.29

.;T;.;.;.

Eigen

Benign

0.074

Eigen_PC

Benign

0.089

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.81

T;T;T;T;T

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.0091

T;T;T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.4

.;L;L;.;.

PhyloP100

2.3

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.6

.;N;N;.;N

REVEL

Uncertain

0.37

Sift

Benign

0.071

.;T;T;.;D

Sift4G

Benign

0.10

T;T;T;T;T

Polyphen

0.98

.;D;.;.;.

Vest4

0.12, 0.12, 0.11

MVP

0.65

MPC

0.48

ClinPred

0.017

GERP RS

4.6

Varity_R

0.22

gMVP

0.56

Mutation Taster

=75/25

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over