7-107563815-GT-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_006348.5(COG5):c.81del(p.Glu27AspfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,586 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: COG5 NM_006348.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.619

Genes affected

COG5 (HGNC:14857): (component of oligomeric golgi complex 5) The protein encoded by this gene is one of eight proteins (Cog1-8) which form a Golgi-localized complex (COG) required for normal Golgi morphology and function. The encoded protein is organized with conserved oligomeric Golgi complex components 6, 7 and 8 into a sub-complex referred to as lobe B. Alternative splicing results in multiple transcript variants. Mutations in this gene result in congenital disorder of glycosylation type 2I.[provided by RefSeq, Jan 2011]

DUS4L (HGNC:21517): (dihydrouridine synthase 4 like) Predicted to enable tRNA dihydrouridine synthase activity. Predicted to be involved in tRNA dihydrouridine synthesis. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 33 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-107563815-GT-G is Pathogenic according to our data. Variant chr7-107563815-GT-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 631993.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COG5	NM_006348.5	c.81del	p.Glu27AspfsTer12	frameshift_variant	1/22	ENST00000297135.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COG5	ENST00000297135.9	c.81del	p.Glu27AspfsTer12	frameshift_variant	1/22	1	NM_006348.5	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247696 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134518

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000905

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461586 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727108

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

COG5-congenital disorder of glycosylation Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 20, 2018	The COG5 c.174delA (p.Glu58AspfsTer12) variant results in a frameshift and is predicted to result in premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The p.Glu58AspfsTer12 variant is reported at a frequency of 0.000015 in the European (non-Finnish) population of the Exome Aggregation Consortium though this is based on one allele in a region of good sequence coverage, so the variant is presumed to be rare. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for congenital disorders of glycosylation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 02, 2021	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 631993). This variant has not been reported in the literature in individuals affected with COG5-related conditions. This variant is present in population databases (rs777937112, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Glu58Aspfs*12) in the COG5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COG5 are known to be pathogenic (PMID: 23228021). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs777937112; hg19: chr7-107204260;