rs199764089

chr19-35302474-G-Achr19-35302474-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002361.4(MAG):c.997G>A(p.Gly333Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,998 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MAG NM_002361.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.11

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.361147).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAG	NM_002361.4	c.997G>A	p.Gly333Arg	missense_variant	7/11	ENST00000392213.8
MAG	NM_001199216.2	c.922G>A	p.Gly308Arg	missense_variant	7/11
MAG	NM_080600.3	c.997G>A	p.Gly333Arg	missense_variant	7/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAG	ENST00000392213.8	c.997G>A	p.Gly333Arg	missense_variant	7/11	1	NM_002361.4	P1
MAG	ENST00000537831.2	c.922G>A	p.Gly308Arg	missense_variant	7/11	1
MAG	ENST00000361922.8	c.997G>A	p.Gly333Arg	missense_variant	7/12	1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251194 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135778

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74316

Gnomad4 AFR AF: 0.0000241

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

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Invitae

Mar 05, 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 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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 572360). This variant has not been reported in the literature in individuals affected with MAG-related conditions. This variant is present in population databases (rs199764089, gnomAD 0.01%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 333 of the MAG protein (p.Gly333Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	22
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.093	T;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.96	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.25
Sift	Uncertain	0.013	D;T;D
Sift4G	Benign	0.082	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.37
MutPred		0.41		Loss of ubiquitination at K328 (P = 0.0557);Loss of ubiquitination at K328 (P = 0.0557);.;
MVP		0.53
MPC		1.4
ClinPred		0.92	D
GERP RS		5.3
Varity_R		0.16
gMVP		0.71

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: rs199764089; hg19: chr19-35793377;