NM_013245.3:c.1107G>A

Variant names:

• chr16-69322595-G-A
• rs1965527680
• NM_013245.3:c.1107G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_013245.3(VPS4A):​c.1107G>A​(p.Met369Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: VPS4A NM_013245.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0770
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07060605).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013245.3. 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
	VPS4A	NM_013245.3	MANE Select	c.1107G>A	p.Met369Ile	missense	Exon 10 of 11	NP_037377.1	Q9UN37

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS4A	ENST00000254950.13	TSL:1 MANE Select	c.1107G>A	p.Met369Ile	missense	Exon 10 of 11	ENSP00000254950.11	Q9UN37
	ENSG00000260914	ENST00000570054.3	TSL:5	c.1179G>A	p.Met393Ile	missense	Exon 10 of 10	ENSP00000461295.3	I3L4J1
	VPS4A	ENST00000566354.1	TSL:1	n.1385G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461594 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727078

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111810

Other (OTH) AF: 0.0000994 AC: 6 AN: 60366

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000624 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	15
DANN	Benign	0.54
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.69
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	-1.3	N
PhyloP100		0.077
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.24	N
REVEL	Uncertain	0.32
Sift	Benign	0.76	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.22
MutPred		0.28		Loss of disorder (P = 0.0359)
MVP		0.39
MPC		0.95
ClinPred		0.037	T
GERP RS		3.5
Varity_R		0.074
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs1965527680; hg19: chr16-69356498;