rs201985838

Positions:

• chr19-35313292-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP7 BS1_Supporting

The NM_002361.4(MAG):​c.1719C>T​(p.Ser573=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000949 in 1,612,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000098 (0 hom.)
• Consequence: MAG NM_002361.4 splice_region, synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.08

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP7: Synonymous conserved (PhyloP=-1.08 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000657 (10/152200) while in subpopulation NFE AF= 0.000147 (10/68020). AF 95% confidence interval is 0.0000791. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAG	NM_002361.4	c.1719C>T	p.Ser573=	splice_region_variant, synonymous_variant	11/11	ENST00000392213.8
MAG	NM_001199216.2	c.1644C>T	p.Ser548=	splice_region_variant, synonymous_variant	11/11
MAG	NM_080600.3	c.*15C>T		splice_region_variant, 3_prime_UTR_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAG	ENST00000392213.8	c.1719C>T	p.Ser573=	splice_region_variant, synonymous_variant	11/11	1	NM_002361.4	P1
MAG	ENST00000537831.2	c.1644C>T	p.Ser548=	splice_region_variant, synonymous_variant	11/11	1
MAG	ENST00000361922.8	c.*15C>T		splice_region_variant, 3_prime_UTR_variant	12/12	1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000402 AC: 10 AN: 248986 Hom.: 0 AF XY: 0.0000446 AC XY: 6 AN XY: 134656

Gnomad AFR exome AF: 0.00

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: 0.0000802

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000979 AC: 143 AN: 1460326 Hom.: 0 Cov.: 31 AF XY: 0.0000757 AC XY: 55 AN XY: 726502

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: 0.000125

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74348

Gnomad4 AFR AF: 0.00

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: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000529

EpiCase AF: 0.000273

EpiControl AF: 0.000119

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

May 07, 2018

This sequence change affects codon 573 of the MAG mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MAG protein. This variant is present in population databases (rs201985838, ExAC 0.008%). This variant has not been reported in the literature in individuals with MAG-related disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.3
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs201985838; hg19: chr19-35804195;