rs3762171

Variant names:

• chr16-70512331-G-A
• rs3762171
• NM_015386.3:c.646C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-70512331-G-A
• chr16-70512331-G-C
• chr16-70512331-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_015386.3(COG4):​c.646C>T​(p.Leu216Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.432 in 1,613,736 control chromosomes in the GnomAD database, including 154,948 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12317 hom., cov: 32)
  • Exomes 𝑓: 0.44 (142631 hom.)
• Consequence: COG4 NM_015386.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.38
• Publications: 29 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 16-70512331-G-A is Benign according to our data. Variant chr16-70512331-G-A is described in ClinVar as Benign. ClinVar VariationId is 95699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

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.646C>T	p.Leu216Leu	synonymous	Exon 5 of 19	NP_056201.2
	COG4	NM_001195139.2		c.634C>T	p.Leu212Leu	synonymous	Exon 5 of 18	NP_001182068.2
	COG4	NM_001365426.1		c.220C>T	p.Leu74Leu	synonymous	Exon 6 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.646C>T	p.Leu216Leu	synonymous	Exon 5 of 19	ENSP00000315775.5
	COG4	ENST00000393612.8	TSL:1	c.646C>T	p.Leu216Leu	synonymous	Exon 5 of 18	ENSP00000377236.5
	COG4	ENST00000530314.5	TSL:1	n.559C>T		non_coding_transcript_exon	Exon 4 of 17

Frequencies

GnomAD3 genomes AF: 0.394 AC: 59812 AN: 151834 Hom.: 12310 Cov.: 32

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.448

Gnomad ASJ AF: 0.427

Gnomad EAS AF: 0.575

Gnomad SAS AF: 0.648

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.420

Gnomad OTH AF: 0.423

GnomAD2 exomes AF: 0.453 AC: 113729 AN: 250938 AF XY: 0.464

Gnomad AFR exome AF: 0.284

Gnomad AMR exome AF: 0.460

Gnomad ASJ exome AF: 0.441

Gnomad EAS exome AF: 0.586

Gnomad FIN exome AF: 0.346

Gnomad NFE exome AF: 0.423

Gnomad OTH exome AF: 0.457

GnomAD4 exome AF: 0.436 AC: 637618 AN: 1461784 Hom.: 142631 Cov.: 49 AF XY: 0.443 AC XY: 321904 AN XY: 727206

African (AFR) AF: 0.294 AC: 9833 AN: 33480

American (AMR) AF: 0.457 AC: 20432 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 11231 AN: 26136

East Asian (EAS) AF: 0.548 AC: 21735 AN: 39696

South Asian (SAS) AF: 0.642 AC: 55392 AN: 86254

European-Finnish (FIN) AF: 0.345 AC: 18418 AN: 53404

Middle Eastern (MID) AF: 0.543 AC: 3130 AN: 5768

European-Non Finnish (NFE) AF: 0.423 AC: 470271 AN: 1111938

Other (OTH) AF: 0.450 AC: 27176 AN: 60392

GnomAD4 genome AF: 0.394 AC: 59847 AN: 151952 Hom.: 12317 Cov.: 32 AF XY: 0.398 AC XY: 29583 AN XY: 74260

African (AFR) AF: 0.286 AC: 11857 AN: 41468

American (AMR) AF: 0.448 AC: 6823 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.427 AC: 1481 AN: 3472

East Asian (EAS) AF: 0.575 AC: 2966 AN: 5158

South Asian (SAS) AF: 0.649 AC: 3120 AN: 4804

European-Finnish (FIN) AF: 0.351 AC: 3704 AN: 10562

Middle Eastern (MID) AF: 0.493 AC: 144 AN: 292

European-Non Finnish (NFE) AF: 0.420 AC: 28536 AN: 67960

Other (OTH) AF: 0.423 AC: 890 AN: 2104

Alfa AF: 0.414 Hom.: 40766

Bravo AF: 0.394

Asia WGS AF: 0.623 AC: 2166 AN: 3478

EpiCase AF: 0.433

EpiControl AF: 0.438

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	12
DANN	Benign	0.74
PhyloP100		3.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3762171; hg19: chr16-70546234; COSMIC: COSV60425505; COSMIC: COSV60425505;