16-69321060-A-G

Variant names:

• chr16-69321060-A-G
• rs1127231
• NM_013245.3:c.861A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_013245.3(VPS4A):​c.861A>G​(p.Lys287Lys) variant causes a synonymous change. The variant allele was found at a frequency of 0.314 in 1,582,594 control chromosomes in the GnomAD database, including 80,385 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.32 (8157 hom., cov: 32)
  • Exomes 𝑓: 0.31 (72228 hom.)
• Consequence: VPS4A NM_013245.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.05
• Publications: 36 publications found

Genes affected

VPS4A (HGNC:13488): (vacuolar protein sorting 4 homolog A) The protein encoded by this gene is a member of the AAA protein family (ATPases associated with diverse cellular activities), and is the homolog of the yeast Vps4 protein. In humans, two paralogs of the yeast protein have been identified. The former share a high degree of aa sequence similarity with each other, and also with yeast Vps4 and mouse Skd1 proteins. The mouse Skd1 (suppressor of K+ transport defect 1) has been shown to be really an yeast Vps4 ortholog. Functional studies indicate that both human paralogs associate with the endosomal compartments, and are involved in intracellular protein trafficking, similar to Vps4 protein in yeast. The gene encoding this paralog has been mapped to chromosome 16; the gene for the other resides on chromosome 18. [provided by RefSeq, Jul 2008]

ENSG00000260914 (HGNC:):

COG8 (HGNC:18623): (component of oligomeric golgi complex 8) This gene encodes a protein that is a component of the conserved oligomeric Golgi (COG) complex, a multiprotein complex that plays a structural role in the Golgi apparatus, and is involved in intracellular membrane trafficking and glycoprotein modification. Mutations in this gene cause congenital disorder of glycosylation, type IIh, a disease that is characterized by under-glycosylated serum proteins, and whose symptoms include severe psychomotor retardation, failure to thrive, seizures, and dairy and wheat product intolerance. [provided by RefSeq, Jul 2008]

COG8 Gene-Disease associations (from GenCC):

• COG8-congenital disorder of glycosylation

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.378 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS4A	NM_013245.3	c.861A>G	p.Lys287Lys	synonymous_variant	Exon 9 of 11	ENST00000254950.13	NP_037377.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS4A	ENST00000254950.13	c.861A>G	p.Lys287Lys	synonymous_variant	Exon 9 of 11	1	NM_013245.3	ENSP00000254950.11
ENSG00000260914	ENST00000570054.3	c.933A>G	p.Lys311Lys	synonymous_variant	Exon 9 of 10	5		ENSP00000461295.3

Frequencies

GnomAD3 genomes AF: 0.319 AC: 48425 AN: 151758 Hom.: 8122 Cov.: 32

Gnomad AFR AF: 0.382

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.0921

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.314

GnomAD2 exomes AF: 0.273 AC: 55461 AN: 202942 AF XY: 0.279

Gnomad AFR exome AF: 0.374

Gnomad AMR exome AF: 0.186

Gnomad ASJ exome AF: 0.255

Gnomad EAS exome AF: 0.0916

Gnomad FIN exome AF: 0.251

Gnomad NFE exome AF: 0.302

Gnomad OTH exome AF: 0.283

GnomAD4 exome AF: 0.314 AC: 448563 AN: 1430718 Hom.: 72228 Cov.: 37 AF XY: 0.315 AC XY: 223509 AN XY: 708718

African (AFR) AF: 0.390 AC: 12715 AN: 32600

American (AMR) AF: 0.195 AC: 8025 AN: 41230

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 6738 AN: 25562

East Asian (EAS) AF: 0.120 AC: 4531 AN: 37876

South Asian (SAS) AF: 0.362 AC: 29477 AN: 81440

European-Finnish (FIN) AF: 0.264 AC: 13493 AN: 51142

Middle Eastern (MID) AF: 0.348 AC: 1996 AN: 5728

European-Non Finnish (NFE) AF: 0.322 AC: 353388 AN: 1096006

Other (OTH) AF: 0.308 AC: 18200 AN: 59134

GnomAD4 genome AF: 0.319 AC: 48516 AN: 151876 Hom.: 8157 Cov.: 32 AF XY: 0.316 AC XY: 23426 AN XY: 74202

African (AFR) AF: 0.383 AC: 15845 AN: 41390

American (AMR) AF: 0.267 AC: 4077 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 933 AN: 3466

East Asian (EAS) AF: 0.0923 AC: 475 AN: 5146

South Asian (SAS) AF: 0.353 AC: 1694 AN: 4804

European-Finnish (FIN) AF: 0.254 AC: 2678 AN: 10556

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.319 AC: 21658 AN: 67926

Other (OTH) AF: 0.324 AC: 683 AN: 2110

Alfa AF: 0.312 Hom.: 14855

Bravo AF: 0.319

Asia WGS AF: 0.287 AC: 997 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.6
DANN	Benign	0.82
PhyloP100		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=85/15	polymorphism (auto)

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: rs1127231; hg19: chr16-69354963; COSMIC: COSV54750156; COSMIC: COSV54750156;