16-70481129-C-T

Position:

• chr16-70481129-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_015386.3(COG4):​c.2251G>A​(p.Asp751Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000176 in 1,613,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: COG4 NM_015386.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.36

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 Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04101017).
• BP6: Variant 16-70481129-C-T is Benign according to our data. Variant chr16-70481129-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 702101.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000125 (19/152270) while in subpopulation EAS AF= 0.0029 (15/5170). AF 95% confidence interval is 0.00179. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COG4	NM_015386.3	c.2251G>A	p.Asp751Asn	missense_variant	19/19	ENST00000323786.10
COG4	NM_001195139.2	c.2176G>A	p.Asp726Asn	missense_variant	18/18
COG4	NM_001365426.1	c.1825G>A	p.Asp609Asn	missense_variant	20/20
COG4	NR_158212.1	n.2210G>A		non_coding_transcript_exon_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COG4	ENST00000323786.10	c.2251G>A	p.Asp751Asn	missense_variant	19/19	1	NM_015386.3	P1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000200 AC: 50 AN: 249872 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135244

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00201

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.0000535

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000181 AC: 265 AN: 1461150 Hom.: 0 Cov.: 33 AF XY: 0.000177 AC XY: 129 AN XY: 726904

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00448

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.000114

Gnomad4 NFE exome AF: 0.0000621

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74448

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00290

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.000170

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000189 AC: 23

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

COG4-congenital disorder of glycosylation Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 20, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 29, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T;T;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.041	T;T;T
MetaSVM	Benign	-0.32	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-4.2	D;.;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.0030	D;.;.
Sift4G	Uncertain	0.0030	D;D;D
Vest4		0.85
MVP		0.67
MPC		0.64
ClinPred		0.34	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.68

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: rs200083914; hg19: chr16-70515032;