Genetic Variant MAG:p.Val161Leu (chr19-35299619-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002361.4(MAG):c.481G>T(p.Val161Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,610,814 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 25)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MAG
NM_002361.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.80

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MAG	NM_002361.4 link	c.481G>T	p.Val161Leu	missense_variant	Exon 5 of 11	ENST00000392213.8	NP_002352.1
MAG	NM_001199216.2 link	c.406G>T	p.Val136Leu	missense_variant	Exon 5 of 11		NP_001186145.1
MAG	NM_080600.3 link	c.481G>T	p.Val161Leu	missense_variant	Exon 5 of 12		NP_542167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAG	ENST00000392213.8 link	c.481G>T	p.Val161Leu	missense_variant	Exon 5 of 11	1	NM_002361.4	ENSP00000376048.2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151898

Hom.:

Cov.:

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000819

AC:

AN:

244142

AF XY:

0.0000151

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1458916

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33412

American (AMR)

AF:

0.00

AC:

AN:

44564

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26060

East Asian (EAS)

AF:

0.00

AC:

AN:

39584

South Asian (SAS)

AF:

0.00

AC:

AN:

85842

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53172

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1110330

Other (OTH)

AF:

0.00

AC:

AN:

60220

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151898

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74172

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41348

American (AMR)

AF:

0.00

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5120

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67968

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000565

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Uncertain

0.067

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;.;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Uncertain

0.50

T;T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

1.9

L;L;.

PhyloP100

6.8

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.33

N;N;N

REVEL

Uncertain

0.45

Sift

Benign

0.091

T;T;T

Sift4G

Uncertain

0.030

D;D;D

Vest4

0.50

ClinPred

0.87

GERP RS

4.6

Varity_R

0.25

gMVP

0.80

Mutation Taster

=56/44

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over