16-46689167-C-T

Position:

• chr16-46689167-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000299138.12(VPS35):​c.-34G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,603,544 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (15 hom.)
• Consequence: VPS35 ENST00000299138.12 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.355

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 16-46689167-C-T is Benign according to our data. Variant chr16-46689167-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 319298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00158 (240/152336) while in subpopulation EAS AF= 0.0274 (142/5182). AF 95% confidence interval is 0.0237. There are 4 homozygotes in gnomad4. There are 120 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 240 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS35	NM_018206.6	c.-34G>A		5_prime_UTR_variant	1/17	ENST00000299138.12	NP_060676.2
VPS35	XM_011523227.4	c.-938G>A		5_prime_UTR_variant	1/17		XP_011521529.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS35	ENST00000299138.12	c.-34G>A		5_prime_UTR_variant	1/17	1	NM_018206.6	ENSP00000299138	P1

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 238 AN: 152218 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0273

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00328 AC: 725 AN: 220946 Hom.: 8 AF XY: 0.00310 AC XY: 374 AN XY: 120732

Gnomad AFR exome AF: 0.0000750

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00108

Gnomad EAS exome AF: 0.0295

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.00152

Gnomad NFE exome AF: 0.000646

Gnomad OTH exome AF: 0.00313

GnomAD4 exome AF: 0.00122 AC: 1766 AN: 1451208 Hom.: 15 Cov.: 31 AF XY: 0.00117 AC XY: 843 AN XY: 720912

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00101

Gnomad4 EAS exome AF: 0.0238

Gnomad4 SAS exome AF: 0.00135

Gnomad4 FIN exome AF: 0.00192

Gnomad4 NFE exome AF: 0.000242

Gnomad4 OTH exome AF: 0.00369

GnomAD4 genome AF: 0.00158 AC: 240 AN: 152336 Hom.: 4 Cov.: 33 AF XY: 0.00161 AC XY: 120 AN XY: 74496

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0274

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00101 Hom.: 1

Bravo AF: 0.00210

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Meier-Gorlin syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Parkinson disease 17 Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs3743928; hg19: chr16-46723079;