NM_002361.4:c.409A>G

Variant names:

• chr19-35295975-A-G
• rs113328438
• NM_002361.4:c.409A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002361.4(MAG):​c.409A>G​(p.Ile137Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,573,478 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (38 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (20 hom.)
• Consequence: MAG NM_002361.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.37
• Publications: 3 publications found

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]

MAG Gene-Disease associations (from GenCC):

• complex hereditary spastic paraplegia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hereditary spastic paraplegia 75

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002742052).
• BP6: Variant 19-35295975-A-G is Benign according to our data. Variant chr19-35295975-A-G is described in ClinVar as Benign. ClinVar VariationId is 542302.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.01 (1528/152312) while in subpopulation AFR AF = 0.0346 (1437/41568). AF 95% confidence interval is 0.0331. There are 38 homozygotes in GnomAd4. There are 689 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002361.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAG	NM_002361.4	MANE Select	c.409A>G	p.Ile137Val	missense	Exon 4 of 11	NP_002352.1	P20916-1
	MAG	NM_001199216.2		c.334A>G	p.Ile112Val	missense	Exon 4 of 11	NP_001186145.1	P20916-3
	MAG	NM_080600.3		c.409A>G	p.Ile137Val	missense	Exon 4 of 12	NP_542167.1	P20916-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAG	ENST00000392213.8	TSL:1 MANE Select	c.409A>G	p.Ile137Val	missense	Exon 4 of 11	ENSP00000376048.2	P20916-1
	MAG	ENST00000537831.2	TSL:1	c.334A>G	p.Ile112Val	missense	Exon 4 of 11	ENSP00000440695.1	P20916-3
	MAG	ENST00000361922.8	TSL:1	c.409A>G	p.Ile137Val	missense	Exon 4 of 12	ENSP00000355234.4	P20916-2

Frequencies

GnomAD3 genomes AF: 0.00995 AC: 1515 AN: 152194 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0343

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00286 AC: 625 AN: 218356 AF XY: 0.00202

Gnomad AFR exome AF: 0.0346

Gnomad AMR exome AF: 0.00192

Gnomad ASJ exome AF: 0.000140

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000219

Gnomad OTH exome AF: 0.00175

GnomAD4 exome AF: 0.00109 AC: 1556 AN: 1421166 Hom.: 20 Cov.: 32 AF XY: 0.000972 AC XY: 682 AN XY: 701790

African (AFR) AF: 0.0353 AC: 1145 AN: 32410

American (AMR) AF: 0.00183 AC: 73 AN: 40000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23714

East Asian (EAS) AF: 0.00 AC: 0 AN: 38948

South Asian (SAS) AF: 0.000136 AC: 11 AN: 80838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51740

Middle Eastern (MID) AF: 0.00376 AC: 21 AN: 5580

European-Non Finnish (NFE) AF: 0.000130 AC: 142 AN: 1089382

Other (OTH) AF: 0.00280 AC: 164 AN: 58554

GnomAD4 genome AF: 0.0100 AC: 1528 AN: 152312 Hom.: 38 Cov.: 32 AF XY: 0.00925 AC XY: 689 AN XY: 74486

African (AFR) AF: 0.0346 AC: 1437 AN: 41568

American (AMR) AF: 0.00431 AC: 66 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68032

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.00412 Hom.: 21

Bravo AF: 0.0114

ESP6500AA AF: 0.0386 AC: 170

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00325 AC: 394

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary spastic paraplegia 75 (1)
-	-	1	MAG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.4
DANN	Benign	0.77
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.73	N
PhyloP100		1.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.066
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.010	B
Vest4		0.11
MVP		0.32
MPC		0.36
ClinPred		0.00084	T
GERP RS		4.2
Varity_R		0.029
gMVP		0.37
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs113328438; hg19: chr19-35786878;