rs1554707637

chr9-99218128-TGG-TTCA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Strong

The NM_033087.4(ALG2):c.1055_1056delinsTGA(p.Ser352LeufsTer3) variant causes a frameshift change. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S352S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALG2 NM_033087.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.17

Genes affected

ALG2 (HGNC:23159): (ALG2 alpha-1,3/1,6-mannosyltransferase) This gene encodes a member of the glycosyltransferase 1 family. The encoded protein acts as an alpha 1,3 mannosyltransferase, mannosylating Man(2)GlcNAc(2)-dolichol diphosphate and Man(1)GlcNAc(2)-dolichol diphosphate to form Man(3)GlcNAc(2)-dolichol diphosphate. Defects in this gene have been associated with congenital disorder of glycosylation type Ih (CDG-Ii). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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 0.157 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG2	NM_033087.4	c.1055_1056delinsTGA	p.Ser352LeufsTer3	frameshift_variant	2/2	ENST00000476832.2
ALG2	XM_047423996.1	c.776_777delinsTGA	p.Ser259LeufsTer3	frameshift_variant	2/2
ALG2	NR_024532.2	n.1262_1263delinsTGA		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG2	ENST00000476832.2	c.1055_1056delinsTGA	p.Ser352LeufsTer3	frameshift_variant	2/2	1	NM_033087.4	P1
ALG2	ENST00000319033.7	c.776_777delinsTGA	p.Ser259LeufsTer3	frameshift_variant	2/2	1
ALG2	ENST00000238477.5	c.*797_*798delinsTGA		3_prime_UTR_variant, NMD_transcript_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 07, 2022

Variant summary: ALG2 c.1055_1056delinsTGA (p.Ser352LeufsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein in the Glycosyl transferase, family 1 domain (IPR001296). Although this truncation is not predicted to cause absense of the protein through nonsense mediated decay, and truncations downstream of this position have been classified as uncertain significance in ClinVar (1053713), the variant may potentially alter protein function by altering the last 65 amino acids in the protein sequence. The variant was absent in 281616 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1055_1056delinsTGA in individuals affected with Congenital Disorder Of Glycosylation, Type 1i and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as of uncertain significance. Based on the evidence outlined above, the variant was classified as VUS. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2021

Not expected to trigger nonsense-mediated mRNA decay Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

ALG2-congenital disorder of glycosylation;C4015597:Congenital myasthenic syndrome 14 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 05, 2023

This sequence change creates a premature translational stop signal (p.Ser352Leufs*3) in the ALG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 65 amino acid(s) of the ALG2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ALG2-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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: rs1554707637; hg19: chr9-101980411;