NM_002361.4:c.116C>T

Variant names:

• chr19-35295682-C-T
• rs201798784
• NM_002361.4:c.116C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002361.4(MAG):​c.116C>T​(p.Ser39Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,692 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MAG NM_002361.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.54

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2629612).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAG	NM_002361.4	c.116C>T	p.Ser39Phe	missense_variant	Exon 4 of 11	ENST00000392213.8	NP_002352.1
MAG	NM_001199216.2	c.41C>T	p.Ser14Phe	missense_variant	Exon 4 of 11		NP_001186145.1
MAG	NM_080600.3	c.116C>T	p.Ser39Phe	missense_variant	Exon 4 of 12		NP_542167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAG	ENST00000392213.8	c.116C>T	p.Ser39Phe	missense_variant	Exon 4 of 11	1	NM_002361.4	ENSP00000376048.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460692 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726746

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 75 Uncertain:1

Feb 16, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine with phenylalanine at codon 39 of the MAG protein (p.Ser39Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MAG-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.052	.;T;.;.;.;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.26	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.26	.;N;N;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.12	.;N;N;.;.;N
REVEL	Benign	0.19
Sift	Benign	0.15	.;T;T;.;.;T
Sift4G	Benign	0.093	T;T;T;T;T;T
Polyphen		0.94	.;P;.;.;.;.
Vest4		0.41, 0.41, 0.44, 0.46
MutPred		0.47		.;Gain of glycosylation at T36 (P = 0.1469);Gain of glycosylation at T36 (P = 0.1469);Gain of glycosylation at T36 (P = 0.1469);Gain of glycosylation at T36 (P = 0.1469);.;
MVP		0.62
MPC		0.94
ClinPred		0.82	D
GERP RS		5.4
Varity_R		0.19
gMVP		0.70

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: rs201798784; hg19: chr19-35786585;