rs1471804208

Positions:

• chr19-35299806-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_002361.4(MAG):​c.668A>G​(p.Asn223Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000678 in 147,538 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 0.0000068 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAG NM_002361.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.72

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 3 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity MAG_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40324467).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAG	NM_002361.4	c.668A>G	p.Asn223Ser	missense_variant	5/11	ENST00000392213.8	NP_002352.1
MAG	NM_001199216.2	c.593A>G	p.Asn198Ser	missense_variant	5/11		NP_001186145.1
MAG	NM_080600.3	c.668A>G	p.Asn223Ser	missense_variant	5/12		NP_542167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAG	ENST00000392213.8	c.668A>G	p.Asn223Ser	missense_variant	5/11	1	NM_002361.4	ENSP00000376048.2
MAG	ENST00000537831.2	c.593A>G	p.Asn198Ser	missense_variant	5/11	1		ENSP00000440695.1
MAG	ENST00000361922.8	c.668A>G	p.Asn223Ser	missense_variant	5/12	1		ENSP00000355234.4
MAG	ENST00000597035.5	c.*252A>G		downstream_gene_variant		4		ENSP00000473245.1

Frequencies

GnomAD3 genomes AF: 0.00000678 AC: 1 AN: 147538 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.0000252

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1387088 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 684172

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000678 AC: 1 AN: 147538 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 71754

Gnomad4 AFR AF: 0.0000252

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 75 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 12, 2022

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 475609). This variant has not been reported in the literature in individuals affected with MAG-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 223 of the MAG protein (p.Asn223Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.;.
Eigen	Benign	0.096
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.40	T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.1	M;M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.29
Sift	Benign	0.082	T;T;T
Sift4G	Benign	0.095	T;T;T
Polyphen		0.51	P;.;.
Vest4		0.35
MutPred		0.72		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;
MVP		0.78
MPC		0.52
ClinPred		0.82	D
GERP RS		4.3
Varity_R		0.31
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1471804208; hg19: chr19-35790709;