rs1555763342

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 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
• 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: Likely_pathogenic. The variant received 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 VariationId is 435794.Status of the report is criteria_provided_single_submitter, 1 stars.

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.416-6_418dupGTATAGACA	p.Asn139_Thr140insSerIleAsp	disruptive_inframe_insertion	Exon 5 of 11	NP_002352.1	P20916-1
	MAG	NM_001199216.2		c.341-6_343dupGTATAGACA	p.Asn114_Thr115insSerIleAsp	disruptive_inframe_insertion	Exon 5 of 11	NP_001186145.1	P20916-3
	MAG	NM_080600.3		c.416-6_418dupGTATAGACA	p.Asn139_Thr140insSerIleAsp	disruptive_inframe_insertion	Exon 5 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.416-7_416-6insGTATAGACA		splice_region intron	N/A	ENSP00000376048.2	P20916-1
	MAG	ENST00000537831.2	TSL:1	c.341-7_341-6insGTATAGACA		splice_region intron	N/A	ENSP00000440695.1	P20916-3
	MAG	ENST00000361922.8	TSL:1	c.416-7_416-6insGTATAGACA		splice_region intron	N/A	ENSP00000355234.4	P20916-2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 28

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-3.3

Splicing

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

Other links and lift over

dbSNP: rs1555763342; hg19: chr19-35790450;