rs1555763342

Variant names:

• chr19-35299547-C-CGTATAGACA
• rs1555763342
• NM_002361.4:c.416-6_418dupGTATAGACA

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_002361.4(MAG):​c.416-6_418dupGTATAGACA​(p.Asn139_Thr140insSerIleAsp) variant causes a disruptive inframe insertion 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 disruptive_inframe_insertion
• 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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_002361.4.
• 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 rank	MANE	Protein	UniProt
MAG	NM_002361.4	c.416-6_418dupGTATAGACA	p.Asn139_Thr140insSerIleAsp	disruptive_inframe_insertion	Exon 5 of 11	ENST00000392213.8	NP_002352.1
MAG	NM_001199216.2	c.341-6_343dupGTATAGACA	p.Asn114_Thr115insSerIleAsp	disruptive_inframe_insertion	Exon 5 of 11		NP_001186145.1
MAG	NM_080600.3	c.416-6_418dupGTATAGACA	p.Asn139_Thr140insSerIleAsp	disruptive_inframe_insertion	Exon 5 of 12		NP_542167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAG	ENST00000392213.8	c.416-7_416-6insGTATAGACA		splice_region_variant, intron_variant	Intron 4 of 10	1	NM_002361.4	ENSP00000376048.2

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

Apr 22, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;