19-35300381-G-T

Variant names:

• chr19-35300381-G-T
• rs370453303
• NM_002361.4:c.947G>T

Variant summary

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

The NM_002361.4(MAG):​c.947G>T​(p.Arg316Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,430,034 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MAG NM_002361.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.03

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAG	NM_002361.4	c.947G>T	p.Arg316Leu	missense_variant	Exon 6 of 11	ENST00000392213.8	NP_002352.1
MAG	NM_001199216.2	c.872G>T	p.Arg291Leu	missense_variant	Exon 6 of 11		NP_001186145.1
MAG	NM_080600.3	c.947G>T	p.Arg316Leu	missense_variant	Exon 6 of 12		NP_542167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAG	ENST00000392213.8	c.947G>T	p.Arg316Leu	missense_variant	Exon 6 of 11	1	NM_002361.4	ENSP00000376048.2
MAG	ENST00000537831.2	c.872G>T	p.Arg291Leu	missense_variant	Exon 6 of 11	1		ENSP00000440695.1
MAG	ENST00000361922.8	c.947G>T	p.Arg316Leu	missense_variant	Exon 6 of 12	1		ENSP00000355234.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000876 AC: 2 AN: 228398 Hom.: 0 AF XY: 0.00000799 AC XY: 1 AN XY: 125136

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000590

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1430034 Hom.: 0 Cov.: 32 AF XY: 0.00000282 AC XY: 2 AN XY: 708556

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000453

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: 0.00

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 75 Uncertain:1

Apr 15, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with leucine at codon 316 of the MAG protein (p.Arg316Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. 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 disease. Algorithms developed to predict the effect of missense changes on protein structure and function 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. -

Inborn genetic diseases Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.947G>T (p.R316L) alteration is located in exon 6 (coding exon 4) of the MAG gene. This alteration results from a G to T substitution at nucleotide position 947, causing the arginine (R) at amino acid position 316 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;.;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.83	T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.1	L;L;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-4.1	D;D;D
REVEL	Uncertain	0.41
Sift	Benign	0.048	D;T;T
Sift4G	Uncertain	0.043	D;D;D
Polyphen		0.72	P;.;.
Vest4		0.55
MutPred		0.63		Loss of catalytic residue at R316 (P = 0.087);Loss of catalytic residue at R316 (P = 0.087);.;
MVP		0.70
MPC		0.95
ClinPred		0.96	D
GERP RS		2.5
Varity_R		0.43
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: rs370453303; hg19: chr19-35791284; COSMIC: COSV62702322; COSMIC: COSV62702322;