16-46659709-C-CA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_018206.6(VPS35):c.*762_*763insT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 143,222 control chromosomes in the GnomAD database, including 1,413 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1413 hom., cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: VPS35 NM_018206.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.88

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 -10 ACMG points.

• BP6: Variant 16-46659709-C-CA is Benign according to our data. Variant chr16-46659709-C-CA is described in ClinVar as [Likely_benign]. Clinvar id is 319266.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS35	NM_018206.6	c.*762_*763insT		3_prime_UTR_variant	17/17	ENST00000299138.12
VPS35	XM_005256045.4	c.*762_*763insT		3_prime_UTR_variant	15/15
VPS35	XM_011523227.4	c.*762_*763insT		3_prime_UTR_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS35	ENST00000299138.12	c.*762_*763insT		3_prime_UTR_variant	17/17	1	NM_018206.6	P1
VPS35	ENST00000568784.6	c.*3823_*3824insT		3_prime_UTR_variant, NMD_transcript_variant	17/17	1
VPS35	ENST00000647959.1	c.*3216_*3217insT		3_prime_UTR_variant, NMD_transcript_variant	18/18

Frequencies

GnomAD3 genomes AF: 0.127 AC: 18111 AN: 143154 Hom.: 1405 Cov.: 30

Gnomad AFR AF: 0.0345

Gnomad AMI AF: 0.0606

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.0646

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.126

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 FIN exome AF: 0.00

GnomAD4 genome AF: 0.127 AC: 18136 AN: 143222 Hom.: 1413 Cov.: 30 AF XY: 0.128 AC XY: 8860 AN XY: 69468

Gnomad4 AFR AF: 0.0344

Gnomad4 AMR AF: 0.230

Gnomad4 ASJ AF: 0.112

Gnomad4 EAS AF: 0.286

Gnomad4 SAS AF: 0.122

Gnomad4 FIN AF: 0.144

Gnomad4 NFE AF: 0.145

Gnomad4 OTH AF: 0.136

Bravo AF: 0.128

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Parkinson Disease, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs34926621; hg19: chr16-46693621;