19-35295422-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The NM_002361.4(MAG):​c.14C>T​(p.Thr5Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T5T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00091 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

MAG
NM_002361.4 missense

Scores

7
12

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.45
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0114637315).
BP6
Variant 19-35295422-C-T is Benign according to our data. Variant chr19-35295422-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 704256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000913 (139/152264) while in subpopulation AFR AF= 0.00327 (136/41534). AF 95% confidence interval is 0.00283. There are 0 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAGNM_002361.4 linkc.14C>T p.Thr5Met missense_variant Exon 3 of 11 ENST00000392213.8 NP_002352.1 P20916-1Q53ES7
MAGNM_080600.3 linkc.14C>T p.Thr5Met missense_variant Exon 3 of 12 NP_542167.1 P20916-2
MAGNM_001199216.2 linkc.-85-33C>T intron_variant Intron 2 of 10 NP_001186145.1 P20916-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MAGENST00000392213.8 linkc.14C>T p.Thr5Met missense_variant Exon 3 of 11 1 NM_002361.4 ENSP00000376048.2 P20916-1

Frequencies

GnomAD3 genomes
AF:
0.000920
AC:
140
AN:
152146
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00331
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000211
AC:
53
AN:
251400
Hom.:
0
AF XY:
0.000169
AC XY:
23
AN XY:
135864
show subpopulations
Gnomad AFR exome
AF:
0.00283
Gnomad AMR exome
AF:
0.0000868
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000766
AC:
112
AN:
1461804
Hom.:
0
Cov.:
31
AF XY:
0.0000633
AC XY:
46
AN XY:
727208
show subpopulations
Gnomad4 AFR exome
AF:
0.00269
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.000199
GnomAD4 genome
AF:
0.000913
AC:
139
AN:
152264
Hom.:
0
Cov.:
32
AF XY:
0.000793
AC XY:
59
AN XY:
74442
show subpopulations
Gnomad4 AFR
AF:
0.00327
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000160
Hom.:
0
Bravo
AF:
0.00106
ESP6500AA
AF:
0.00227
AC:
10
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000272
AC:
33

ClinVar

Significance: Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Jun 21, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: MAG c.14C>T (p.Thr5Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251400 control chromosomes, predominantly at a frequency of 0.0028 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in MAG causing Hereditary Spastic Paraplegia 75 phenotype. To our knowledge, no occurrence of c.14C>T in individuals affected with Hereditary Spastic Paraplegia 75 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 704256). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary spastic paraplegia 75 Benign:1
Jan 06, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1
Oct 07, 2024
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.11
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.052
T;.;.;.
Eigen
Uncertain
0.24
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Uncertain
0.88
D;D;D;D
M_CAP
Benign
0.039
D
MetaRNN
Benign
0.011
T;T;T;T
MetaSVM
Benign
-0.71
T
MutationAssessor
Benign
1.1
L;L;.;.
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
1.4
N;N;.;.
REVEL
Benign
0.17
Sift
Uncertain
0.015
D;D;.;.
Sift4G
Benign
0.066
T;T;T;T
Polyphen
1.0
D;.;.;.
Vest4
0.63
MVP
0.69
MPC
1.1
ClinPred
0.030
T
GERP RS
5.8
Varity_R
0.054
gMVP
0.27

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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.

Other links and lift over

dbSNP: rs149262142; hg19: chr19-35786325; COSMIC: COSV62698827; API