chr4-177442248-C-CCCGCAT

Variant names:

• chr4-177442248-C-CCCGCAT
• rs386833418
• NM_000027.4:c.127_127+1insATGCGG

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4 PP5

The NM_000027.4(AGA):​c.127_127+1insATGCGG​(p.Ala42_Ala43insAspAla) variant causes a conservative inframe insertion, splice region 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 (no stars). Synonymous variant affecting the same amino acid position (i.e. A43A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AGA NM_000027.4 conservative_inframe_insertion, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 3.33
• Publications: 1 publications found

Genes affected

AGA (HGNC:318): (aspartylglucosaminidase) This gene encodes a member of the N-terminal nucleophile (Ntn) hydrolase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta chains that comprise the mature enzyme. This enzyme is involved in the catabolism of N-linked oligosaccharides of glycoproteins. It cleaves asparagine from N-acetylglucosamines as one of the final steps in the lysosomal breakdown of glycoproteins. Mutations in this gene are associated with the lysosomal storage disease aspartylglycosaminuria that results in progressive neurodegeneration. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is subject to proteolytic processing. [provided by RefSeq, Nov 2015]

AGA Gene-Disease associations (from GenCC):

• aspartylglucosaminuria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000027.4.
• PP5: Variant 4-177442248-C-CCCGCAT is Pathogenic according to our data. Variant chr4-177442248-C-CCCGCAT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 226.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGA	NM_000027.4	c.127_127+1insATGCGG	p.Ala42_Ala43insAspAla	conservative_inframe_insertion, splice_region_variant	Exon 1 of 9	ENST00000264595.7	NP_000018.2
AGA	NM_001171988.2	c.127_127+1insATGCGG	p.Ala42_Ala43insAspAla	conservative_inframe_insertion, splice_region_variant	Exon 1 of 9		NP_001165459.1
AGA	XM_047449722.1	c.127_127+1insATGCGG	p.Ala42_Ala43insAspAla	conservative_inframe_insertion, splice_region_variant	Exon 1 of 7		XP_047305678.1
AGA	NR_033655.2	n.189_189+1insATGCGG		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGA	ENST00000264595.7	c.127_127+1insATGCGG	p.Ala42_Ala43insAspAla	conservative_inframe_insertion, splice_region_variant	Exon 1 of 9	1	NM_000027.4	ENSP00000264595.2
AGA	ENST00000506853.5	n.161_161+1insATGCGG		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 6	2
AGA	ENST00000510955.5	n.161_161+1insATGCGG		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 4	2
AGA	ENST00000511231.1	n.161_161+1insATGCGG		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Aspartylglucosaminuria Pathogenic:2

Sep 01, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs386833418; hg19: chr4-178363402;