16-70496367-C-T

Variant names:

• chr16-70496367-C-T
• rs1555575860
• NM_015386.3:c.1546G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS1 PM2 PP3 PP5_Very_Strong

The NM_015386.3(COG4):​c.1546G>A​(p.Gly516Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COG4 NM_015386.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 7.71
• Publications: 1 publications found

Genes affected

COG4 (HGNC:18620): (component of oligomeric golgi complex 4) The protein encoded by this gene is a component of an oligomeric protein complex involved in the structure and function of the Golgi apparatus. Defects in this gene may be a cause of congenital disorder of glycosylation type IIj. Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Aug 2010]

COG4 Gene-Disease associations (from GenCC):

• COG4-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen, PanelApp Australia, Ambry Genetics
• microcephalic osteodysplastic dysplasia, Saul-Wilson type

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

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS1: Transcript NM_015386.3 (COG4) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824
• PP5: Variant 16-70496367-C-T is Pathogenic according to our data. Variant chr16-70496367-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 449730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015386.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COG4	NM_015386.3	MANE Select	c.1546G>A	p.Gly516Arg	missense	Exon 12 of 19	NP_056201.2
	COG4	NM_001195139.2		c.1534G>A	p.Gly512Arg	missense	Exon 12 of 18	NP_001182068.2
	COG4	NM_001365426.1		c.1120G>A	p.Gly374Arg	missense	Exon 13 of 20	NP_001352355.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COG4	ENST00000323786.10	TSL:1 MANE Select	c.1546G>A	p.Gly516Arg	missense	Exon 12 of 19	ENSP00000315775.5
	COG4	ENST00000393612.8	TSL:1	c.1546G>A	p.Gly516Arg	missense	Exon 12 of 18	ENSP00000377236.5
	COG4	ENST00000530314.5	TSL:1	n.2225G>A		non_coding_transcript_exon	Exon 10 of 17

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Nov 23, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a significant increase in core proteins of HSPGs accumulation on the cell surface of G516R mutant cell lines and increased secretion of the SIL1 protein; findings which support a gain of function effect of the G516R variant (Sumya et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34603392, 31949312, 30290151, 33688625, 34595172, 35455576, 36393834)

Mar 31, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 08, 2020

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant appears to occur de novo in an individual tested at Athena Diagnostics and in multiple individuals with clinical features consistent with autosomal dominant Saul-Wilson syndrome (PMID 30290151). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools yielded predictions that this amino acid change may be damaging to the protein.This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.

Microcephalic osteodysplastic dysplasia, Saul-Wilson type Pathogenic:2 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Jul 11, 2019

SIB Swiss Institute of Bioinformatics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Pathogenic for Saul-Wilson syndrome, autosomal dominant. The following ACMG Tag(s) were applied: PM2; PS4-Moderate; PM6-Strong; PP3; PS3

Nov 29, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Inborn genetic diseases Pathogenic:1

Sep 17, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1546G>A (p.G516R) alteration is located in exon 12 (coding exon 12) of the COG4 gene. This alteration results from a G to A substitution at nucleotide position 1546, causing the glycine (G) at amino acid position 516 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). The p.G516R alteration has been reported as a recurrent de novo alteration in several patients with Saul-Wilson syndrome (Ferreira, 2018). This amino acid position is highly conserved in available vertebrate species. Fibroblasts from patients with the p.G516R alteration have been shown to have abnormal Golgi morphology and decreased Golgi volume compared to control samples. Glycan analysis and glycosylation status were not measurably different between patients and controls; however there was evidence of altered Golgi-dependent glycosylation and abnormal Golgi trafficking in patients (Ferreira, 2018) . The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.

COG4-congenital disorder of glycosylation Pathogenic:1

Aug 23, 2017

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This individual has been reported in PMID: 30290151.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.049	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.66	T
PhyloP100		7.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.38
Sift	Benign	0.045	D
Sift4G	Benign	0.12	T
Vest4		0.91
MVP		0.68
MPC		0.70
ClinPred		0.98	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.79
Mutation Taster		=13/87	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555575860; hg19: chr16-70530270; COSMIC: COSV60421914; COSMIC: COSV60421914;