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:8 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P, ClinGen
• 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

Sel.	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	J3KNI1
	COG4	NM_001195139.2		c.1534G>A	p.Gly512Arg	missense	Exon 12 of 18	NP_001182068.2	A0A6I8PIQ6
	COG4	NM_001365426.1		c.1120G>A	p.Gly374Arg	missense	Exon 13 of 20	NP_001352355.1

Ensembl Transcripts

Sel.	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	J3KNI1
	COG4	ENST00000393612.8	TSL:1	c.1546G>A	p.Gly516Arg	missense	Exon 12 of 18	ENSP00000377236.5	A0A0A0MS45
	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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
2	-	-	Microcephalic osteodysplastic dysplasia, Saul-Wilson type (3)
1	-	-	COG4-congenital disorder of glycosylation (1)
1	-	-	Inborn genetic diseases (1)

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;