16-46660189-G-T

Variant summary

Our verdict is Benign. Variant got -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, single submitter U:1
• Conservation: PhyloP100: -0.865

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]

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 12. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 793 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS35	NM_018206.6	c.*283C>A		3_prime_UTR_variant	17/17	ENST00000299138.12
VPS35	XM_005256045.4	c.*283C>A		3_prime_UTR_variant	15/15
VPS35	XM_011523227.4	c.*283C>A		3_prime_UTR_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS35	ENST00000299138.12	c.*283C>A		3_prime_UTR_variant	17/17	1	NM_018206.6	P1
VPS35	ENST00000568784.6	c.*3344C>A		3_prime_UTR_variant, NMD_transcript_variant	17/17	1
VPS35	ENST00000647959.1	c.*2737C>A		3_prime_UTR_variant, NMD_transcript_variant	18/18

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

Gnomad4 AFR exome AF: 0.00424

Gnomad4 AMR exome AF: 0.0164

Gnomad4 ASJ exome AF: 0.0566

Gnomad4 EAS exome AF: 0.108

Gnomad4 SAS exome AF: 0.293

Gnomad4 FIN exome AF: 0.0710

Gnomad4 NFE exome AF: 0.0368

Gnomad4 OTH exome AF: 0.0654

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

Gnomad4 AFR AF: 0.00557

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.00741

Gnomad4 EAS AF: 0.0219

Gnomad4 SAS AF: 0.0316

Gnomad4 FIN AF: 0.0239

Gnomad4 NFE AF: 0.00795

Gnomad4 OTH AF: 0.0137

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Parkinson disease 17 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	0.068
Dann	Benign	0.28

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: rs199765664; hg19: chr16-46694101;