rs1555763342

chr19-35299547-C-CGTATAGACA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_002361.4(MAG):c.416-6_418dup variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 28)
• Consequence: MAG NM_002361.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -3.34

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-35299547-C-CGTATAGACA is Pathogenic according to our data. Variant chr19-35299547-C-CGTATAGACA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 435794.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAG	NM_002361.4	c.416-6_418dup		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000392213.8
MAG	NM_001199216.2	c.341-6_343dup		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
MAG	NM_080600.3	c.416-6_418dup		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAG	ENST00000392213.8	c.416-6_418dup		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002361.4	P1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 28

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 22, 2021

DNA sequence analysis of the MAG gene demonstrated a 9 base pair duplication involving nucleotides in intron 5 and exon 6, c.416-6_418dup. This sequence change is absent from known population databases (gnomAD). The impact of this variant on splicing is unclear, however it is possible this duplication results in an in-frame insertion of three amino acid residues. This sequence change does not appear to have been previously described in patients with MAG-related disorders and has also not been described as a known benign sequence change in the MAG gene. Targeted sequence analysis of the MAG variant in this family indicated that this homozygous variant co-segregated with disease in this individual’s affected mother, sister, and brother. Taken together, this variant has been re-classified as likely pathogenic. Functional studies have not been performed to prove this conclusively. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555763342; hg19: chr19-35790450;