3-184242642-T-TC

Variant names:

• chr3-184242642-T-TC
• NM_005787.6:c.1188dupG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_005787.6(ALG3):​c.1188dupG​(p.Asn397GlufsTer99) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALG3 NM_005787.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.87
• Publications: 0 publications found

Genes affected

ALG3 (HGNC:23056): (ALG3 alpha-1,3- mannosyltransferase) This gene encodes a member of the ALG3 family. The encoded protein catalyses the addition of the first dol-P-Man derived mannose in an alpha 1,3 linkage to Man5GlcNAc2-PP-Dol. Defects in this gene have been associated with congenital disorder of glycosylation type Id (CDG-Id) characterized by abnormal N-glycosylation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2008]

ALG3 Gene-Disease associations (from GenCC):

• ALG3-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0979 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-184242642-T-TC is Pathogenic according to our data. Variant chr3-184242642-T-TC is described in ClinVar as Pathogenic. ClinVar VariationId is 2000151.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005787.6. 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
	ALG3	NM_005787.6	MANE Select	c.1188dupG	p.Asn397GlufsTer99	frameshift	Exon 9 of 9	NP_005778.1	Q92685-1
	ALG3	NM_001006941.2		c.1044dupG	p.Asn349GlufsTer99	frameshift	Exon 9 of 9	NP_001006942.1	Q92685-2
	ALG3	NR_024533.1		n.1119dupG		non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG3	ENST00000397676.8	TSL:1 MANE Select	c.1188dupG	p.Asn397GlufsTer99	frameshift	Exon 9 of 9	ENSP00000380793.3	Q92685-1
	ALG3	ENST00000445626.6	TSL:1	c.1044dupG	p.Asn349GlufsTer73	frameshift	Exon 9 of 9	ENSP00000402744.2	Q92685-2
	ALG3	ENST00000411922.5	TSL:1	n.*764dupG		non_coding_transcript_exon	Exon 8 of 8	ENSP00000394917.1	F8WE30

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	ALG3-congenital disorder of glycosylation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chr3-183960430;