19-35299600-G-T

Variant names:

• chr19-35299600-G-T
• rs3746248
• NM_002361.4:c.462G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002361.4(MAG):​c.462G>T​(p.Glu154Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E154E) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MAG NM_002361.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0520
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2905389).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAG	NM_002361.4	c.462G>T	p.Glu154Asp	missense_variant	Exon 5 of 11	ENST00000392213.8	NP_002352.1
MAG	NM_001199216.2	c.387G>T	p.Glu129Asp	missense_variant	Exon 5 of 11		NP_001186145.1
MAG	NM_080600.3	c.462G>T	p.Glu154Asp	missense_variant	Exon 5 of 12		NP_542167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAG	ENST00000392213.8	c.462G>T	p.Glu154Asp	missense_variant	Exon 5 of 11	1	NM_002361.4	ENSP00000376048.2

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454240 Hom.: 0 Cov.: 35 AF XY: 0.00000139 AC XY: 1 AN XY: 721890

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33262

American (AMR) AF: 0.00 AC: 0 AN: 44370

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39374

South Asian (SAS) AF: 0.00 AC: 0 AN: 85676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106712

Other (OTH) AF: 0.00 AC: 0 AN: 59948

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.0092	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	.;T;.;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.80	T;T;T;T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.29	T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.2	.;M;M;.;.
PhyloP100		-0.052
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.80	.;N;N;.;N
REVEL	Uncertain	0.37
Sift	Benign	0.15	.;T;T;.;T
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.98	.;D;.;.;.
Vest4		0.13, 0.12, 0.12
MutPred		0.52		.;Loss of glycosylation at T153 (P = 0.1357);Loss of glycosylation at T153 (P = 0.1357);Loss of glycosylation at T153 (P = 0.1357);.;
MVP		0.85
MPC		1.0
ClinPred		0.52	D
GERP RS		1.9
Varity_R		0.19
gMVP		0.48
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs3746248; hg19: chr19-35790503;