3-184245796-CCA-TCT

Variant names:

• chr3-184245796-CCA-TCT
• NM_005787.6:c.211_213delTGGinsAGA
• ALG3 p.Trp71Arg

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP2 PP3

The NM_005787.6(ALG3):​c.211_213delTGGinsAGA​(p.Trp71Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALG3 NM_005787.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.73
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_005787.6
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: -0.31675 (below the threshold of 3.09). Trascript score misZ: 0.74965 (below the threshold of 3.09). GenCC associations: The gene is linked to ALG3-congenital disorder of glycosylation.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.211_213delTGGinsAGA	p.Trp71Arg	missense	N/A	NP_005778.1	Q92685-1
	ALG3	NM_001006941.2		c.67_69delTGGinsAGA	p.Trp23Arg	missense	N/A	NP_001006942.1	Q92685-2
	ALG3	NR_024534.1		n.205_207delTGGinsAGA		non_coding_transcript_exon	Exon 2 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG3	ENST00000397676.8	TSL:1 MANE Select	c.211_213delTGGinsAGA	p.Trp71Arg	missense	N/A	ENSP00000380793.3	Q92685-1
	ALG3	ENST00000445626.6	TSL:1	c.67_69delTGGinsAGA	p.Trp23Arg	missense	N/A	ENSP00000402744.2	Q92685-2
	ALG3	ENST00000482048.1	TSL:1	n.200_202delTGGinsAGA		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr3-183963584;