NM_018206.6:c.*283C>A

Variant names:

• chr16-46660189-G-T
• rs199765664
• NM_018206.6:c.*283C>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_018206.6(VPS35):​c.*283C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (21 hom., cov: 12)
  • Exomes 𝑓: 0.080 (247 hom.)
  • Failed GnomAD Quality Control
• Consequence: VPS35 NM_018206.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.865
• Publications: 0 publications found

Genes affected

VPS35 (HGNC:13487): (VPS35 retromer complex component) This gene belongs to a group of vacuolar protein sorting (VPS) genes. The encoded protein is a component of a large multimeric complex, termed the retromer complex, involved in retrograde transport of proteins from endosomes to the trans-Golgi network. The close structural similarity between the yeast and human proteins that make up this complex suggests a similarity in function. Expression studies in yeast and mammalian cells indicate that this protein interacts directly with VPS35, which serves as the core of the retromer complex. [provided by RefSeq, Jul 2008]

VPS35 Gene-Disease associations (from GenCC):

• Parkinson disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Parkinson disease 17

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• hereditary late onset Parkinson disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual disability

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00885 (795/89846) while in subpopulation SAS AF = 0.0316 (68/2150). AF 95% confidence interval is 0.0256. There are 21 homozygotes in GnomAd4. There are 425 alleles in the male GnomAd4 subpopulation. Median coverage is 12. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 21 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018206.6. 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
	VPS35	NM_018206.6	MANE Select	c.*283C>A		3_prime_UTR	Exon 17 of 17	NP_060676.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS35	ENST00000299138.12	TSL:1 MANE Select	c.*283C>A		3_prime_UTR	Exon 17 of 17	ENSP00000299138.7	Q96QK1
	VPS35	ENST00000568784.6	TSL:1	n.*3344C>A		non_coding_transcript_exon	Exon 17 of 17	ENSP00000456274.2	H3BRJ7
	VPS35	ENST00000568784.6	TSL:1	n.*3344C>A		3_prime_UTR	Exon 17 of 17	ENSP00000456274.2	H3BRJ7

Frequencies

GnomAD3 genomes AF: 0.00883 AC: 793 AN: 89832 Hom.: 21 Cov.: 12

Gnomad AFR AF: 0.00553

Gnomad AMI AF: 0.0184

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.00741

Gnomad EAS AF: 0.0215

Gnomad SAS AF: 0.0311

Gnomad FIN AF: 0.0239

Gnomad MID AF: 0.00926

Gnomad NFE AF: 0.00797

Gnomad OTH AF: 0.0137

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0804 AC: 690 AN: 8580 Hom.: 247 Cov.: 0 AF XY: 0.0942 AC XY: 415 AN XY: 4404

African (AFR) AF: 0.00424 AC: 1 AN: 236

American (AMR) AF: 0.0164 AC: 11 AN: 672

Ashkenazi Jewish (ASJ) AF: 0.0566 AC: 12 AN: 212

East Asian (EAS) AF: 0.108 AC: 39 AN: 360

South Asian (SAS) AF: 0.293 AC: 390 AN: 1330

European-Finnish (FIN) AF: 0.0710 AC: 25 AN: 352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 32

European-Non Finnish (NFE) AF: 0.0368 AC: 181 AN: 4912

Other (OTH) AF: 0.0654 AC: 31 AN: 474

GnomAD4 genome AF: 0.00885 AC: 795 AN: 89846 Hom.: 21 Cov.: 12 AF XY: 0.0106 AC XY: 425 AN XY: 40064

African (AFR) AF: 0.00557 AC: 144 AN: 25870

American (AMR) AF: 0.0118 AC: 77 AN: 6534

Ashkenazi Jewish (ASJ) AF: 0.00741 AC: 19 AN: 2564

East Asian (EAS) AF: 0.0219 AC: 50 AN: 2280

South Asian (SAS) AF: 0.0316 AC: 68 AN: 2150

European-Finnish (FIN) AF: 0.0239 AC: 34 AN: 1420

Middle Eastern (MID) AF: 0.00980 AC: 1 AN: 102

European-Non Finnish (NFE) AF: 0.00795 AC: 375 AN: 47160

Other (OTH) AF: 0.0137 AC: 16 AN: 1168

Alfa AF: 0.000173 Hom.: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Parkinson disease 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.068
DANN	Benign	0.28
PhyloP100		-0.86
Mutation Taster		=100/0	polymorphism

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: rs199765664; hg19: chr16-46694101;