19-35302594-A-C

Variant names:

• chr19-35302594-A-C
• rs142375870
• NM_002361.4:c.1117A>C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_002361.4(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: MAG NM_002361.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.41

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]

ACMG classification

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 rank	MANE	Protein	UniProt
MAG	NM_002361.4	c.1117A>C	p.Ser373Arg	missense_variant	Exon 7 of 11	ENST00000392213.8	NP_002352.1
MAG	NM_001199216.2	c.1042A>C	p.Ser348Arg	missense_variant	Exon 7 of 11		NP_001186145.1
MAG	NM_080600.3	c.1117A>C	p.Ser373Arg	missense_variant	Exon 7 of 12		NP_542167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAG	ENST00000392213.8	c.1117A>C	p.Ser373Arg	missense_variant	Exon 7 of 11	1	NM_002361.4	ENSP00000376048.2
MAG	ENST00000537831.2	c.1042A>C	p.Ser348Arg	missense_variant	Exon 7 of 11	1		ENSP00000440695.1
MAG	ENST00000361922.8	c.1117A>C	p.Ser373Arg	missense_variant	Exon 7 of 12	1		ENSP00000355234.4

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152178 Hom.: 0 Cov.: 32

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: 58 AN: 251468 Hom.: 0 AF XY: 0.000243 AC XY: 33 AN XY: 135916

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.: 0 Cov.: 31 AF XY: 0.000129 AC XY: 94 AN XY: 727244

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: 35 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74452

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.: 0

Bravo AF: 0.000393

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 75 Uncertain:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.040	T;T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.62	N;N;.
PrimateAI	Benign	0.47	T
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	T
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

Other links and lift over

dbSNP: rs142375870; hg19: chr19-35793497;