rs746019074

Positions:

• chr16-5083744-C-CTG

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_019109.5(ALG1):​c.1250_1251insTG​(p.Ala418GlufsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,190 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ALG1 NM_019109.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -1.83

Genes affected

ALG1 (HGNC:18294): (ALG1 chitobiosyldiphosphodolichol beta-mannosyltransferase) The enzyme encoded by this gene catalyzes the first mannosylation step in the biosynthesis of lipid-linked oligosaccharides. This gene is mutated in congenital disorder of glycosylation type Ik. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-5083744-C-CTG is Pathogenic according to our data. Variant chr16-5083744-C-CTG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 424339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG1	NM_019109.5	c.1250_1251insTG	p.Ala418GlufsTer18	frameshift_variant	12/13	ENST00000262374.10
ALG1	NM_001330504.2	c.917_918insTG	p.Ala307GlufsTer18	frameshift_variant	12/13
ALG1	XM_017023457.3	c.1211_1212insTG	p.Ala405GlufsTer18	frameshift_variant	11/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG1	ENST00000262374.10	c.1250_1251insTG	p.Ala418GlufsTer18	frameshift_variant	12/13	1	NM_019109.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000128 AC: 3 AN: 235286 Hom.: 0 AF XY: 0.0000233 AC XY: 3 AN XY: 128800

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000202

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000910

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000553 AC: 8 AN: 1445530 Hom.: 0 Cov.: 34 AF XY: 0.00000695 AC XY: 5 AN XY: 719520

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital disorder of glycosylation Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

May 25, 2017

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 20, 2022

Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 47 amino acids are lost and replaced with 17 incorrect amino acids [Human Gene Mutation Database] (HGMD); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26931382, 26453362) -

ALG1-congenital disorder of glycosylation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 12, 2023

This sequence change creates a premature translational stop signal (p.Ala418Glufs*18) in the ALG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acid(s) of the ALG1 protein. This variant is present in population databases (rs746019074, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with congenital disorders of glycosylation (PMID: 26453362, 26931382). ClinVar contains an entry for this variant (Variation ID: 424339). This variant disrupts the p.Arg438 amino acid residue in ALG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20679665, 26931382). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

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: rs746019074; hg19: chr16-5133745;