chr19-35302594-A-C

Position:

chr19-35302594-A-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The ENST00000392213.8(MAG):c.1117A>C(p.Ser373Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000147 in 1,614,180 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S373S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

MAG
ENST00000392213.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.41

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0404177).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00023 (35/152296) while in subpopulation AMR AF= 0.00118 (18/15308). AF 95% confidence interval is 0.00076. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MAG	NM_002361.4 linkuse as main transcript	c.1117A>C	p.Ser373Arg	missense_variant	7/11	ENST00000392213.8	NP_002352.1
MAG	NM_001199216.2 linkuse as main transcript	c.1042A>C	p.Ser348Arg	missense_variant	7/11		NP_001186145.1
MAG	NM_080600.3 linkuse as main transcript	c.1117A>C	p.Ser373Arg	missense_variant	7/12		NP_542167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAG	ENST00000392213.8 linkuse as main transcript	c.1117A>C	p.Ser373Arg	missense_variant	7/11	1	NM_002361.4	ENSP00000376048	P1	P20916-1
MAG	ENST00000537831.2 linkuse as main transcript	c.1042A>C	p.Ser348Arg	missense_variant	7/11	1		ENSP00000440695		P20916-3
MAG	ENST00000361922.8 linkuse as main transcript	c.1117A>C	p.Ser373Arg	missense_variant	7/12	1		ENSP00000355234		P20916-2

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

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:

0.000162

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000231

AC:

AN:

251468

Hom.:

AF XY:

0.000243

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000607

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000273

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.000138

AC:

202

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000648

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000122

Gnomad4 OTH exome

AF:

0.000430

GnomAD4 genome

AF:

0.000230

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000190

Hom.:

Bravo

AF:

0.000393

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000255

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 75

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 373 of the MAG protein (p.Ser373Arg). This variant is present in population databases (rs142375870, gnomAD 0.06%). This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 28832565, 31402626). ClinVar contains an entry for this variant (Variation ID: 424677). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MAG protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

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

Mar 07, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.74

T;T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.040

T;T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

0.62

N;N;.

MutationTaster

Benign

0.97

D;D;D

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.9

N;N;N

REVEL

Uncertain

0.47

Sift

Benign

0.068

T;T;T

Sift4G

Benign

0.079

T;T;T

Polyphen

0.97

D;.;.

Vest4

0.27

MutPred

0.31

Gain of solvent accessibility (P = 0.0365);Gain of solvent accessibility (P = 0.0365);.;

MVP

0.74

MPC

1.1

ClinPred

0.13

GERP RS

5.1

Varity_R

0.29

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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