16-46660184-G-GT

Position:

• chr16-46660184-G-GT

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_018206.6(VPS35):​c.*287_*288insA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 68,078 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 27)
  • Exomes 𝑓: 0.00095 (5 hom.)
• Consequence: VPS35 NM_018206.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.25

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS35	NM_018206.6	c.*287_*288insA		3_prime_UTR_variant	17/17	ENST00000299138.12	NP_060676.2
VPS35	XM_005256045.4	c.*287_*288insA		3_prime_UTR_variant	15/15		XP_005256102.1
VPS35	XM_011523227.4	c.*287_*288insA		3_prime_UTR_variant	17/17		XP_011521529.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS35	ENST00000299138.12	c.*287_*288insA		3_prime_UTR_variant	17/17	1	NM_018206.6	ENSP00000299138	P1
VPS35	ENST00000568784.6	c.*3348_*3349insA		3_prime_UTR_variant, NMD_transcript_variant	17/17	1		ENSP00000456274
VPS35	ENST00000647959.1	c.*2741_*2742insA		3_prime_UTR_variant, NMD_transcript_variant	18/18			ENSP00000497702

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 34 AN: 22890 Hom.: 1 Cov.: 27

Gnomad AFR AF: 0.00139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00136

Gnomad ASJ AF: 0.00174

Gnomad EAS AF: 0.00123

Gnomad SAS AF: 0.00364

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.00427

GnomAD4 exome AF: 0.000952 AC: 43 AN: 45174 Hom.: 5 Cov.: 0 AF XY: 0.00123 AC XY: 28 AN XY: 22796

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000801

Gnomad4 SAS exome AF: 0.00548

Gnomad4 FIN exome AF: 0.00102

Gnomad4 NFE exome AF: 0.000538

Gnomad4 OTH exome AF: 0.000344

GnomAD4 genome AF: 0.00148 AC: 34 AN: 22904 Hom.: 1 Cov.: 27 AF XY: 0.00225 AC XY: 24 AN XY: 10672

Gnomad4 AFR AF: 0.00138

Gnomad4 AMR AF: 0.00136

Gnomad4 ASJ AF: 0.00174

Gnomad4 EAS AF: 0.00123

Gnomad4 SAS AF: 0.00368

Gnomad4 FIN AF: 0.00330

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.00424

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Parkinson Disease, Dominant Uncertain:1

Uncertain significance, 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: rs369068093; hg19: chr16-46694096;