chr16-70496367-C-G

Position:

• chr16-70496367-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_Very_Strong PM2 PP3 PP5

The ENST00000323786.10(COG4):​c.1546G>C​(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 (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COG4 ENST00000323786.10 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.71

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PS1: Transcript ENST00000323786.10 (COG4) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 449730
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825
• PP5: Variant 16-70496367-C-G is Pathogenic according to our data. Variant chr16-70496367-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 585271.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-70496367-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COG4	NM_015386.3	c.1546G>C	p.Gly516Arg	missense_variant	12/19	ENST00000323786.10	NP_056201.2
COG4	NM_001195139.2	c.1534G>C	p.Gly512Arg	missense_variant	12/18		NP_001182068.2
COG4	NM_001365426.1	c.1120G>C	p.Gly374Arg	missense_variant	13/20		NP_001352355.1
COG4	NR_158212.1	n.1505G>C		non_coding_transcript_exon_variant	12/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COG4	ENST00000323786.10	c.1546G>C	p.Gly516Arg	missense_variant	12/19	1	NM_015386.3	ENSP00000315775	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

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

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.049	T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.64	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.7	N;.
REVEL	Uncertain	0.37
Sift	Benign	0.045	D;.
Sift4G	Benign	0.12	T;T
Vest4		0.91
MVP		0.68
MPC		0.70
ClinPred		0.98	D
GERP RS		6.0
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1555575860; hg19: chr16-70530270;