16-46660184-G-GTTT

Position:

• chr16-46660184-G-GTTT

Variant summary

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

The NM_018206.6(VPS35):​c.*287_*288insAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.013 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00024 (0 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: -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 GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS35	NM_018206.6	c.*287_*288insAAA		3_prime_UTR_variant	17/17	ENST00000299138.12
VPS35	XM_005256045.4	c.*287_*288insAAA		3_prime_UTR_variant	15/15
VPS35	XM_011523227.4	c.*287_*288insAAA		3_prime_UTR_variant	17/17

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00 AC: 296 AN: 22546 Hom.: 0 Cov.: 27 FAILED QC

Gnomad AFR AF: 0.00910

Gnomad AMI AF: 0.0467

Gnomad AMR AF: 0.0307

Gnomad ASJ AF: 0.0125

Gnomad EAS AF: 0.0296

Gnomad SAS AF: 0.0220

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.0221

GnomAD4 exome AF: 0.000244 AC: 11 AN: 45174 Hom.: 0 Cov.: 0 AF XY: 0.000263 AC XY: 6 AN XY: 22796

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000682

Gnomad4 EAS exome AF: 0.000401

Gnomad4 SAS exome AF: 0.000714

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000215

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0132 AC: 297 AN: 22558 Hom.: 0 Cov.: 27 AF XY: 0.0149 AC XY: 156 AN XY: 10494

Gnomad4 AFR AF: 0.00906

Gnomad4 AMR AF: 0.0306

Gnomad4 ASJ AF: 0.0125

Gnomad4 EAS AF: 0.0296

Gnomad4 SAS AF: 0.0232

Gnomad4 FIN AF: 0.0135

Gnomad4 NFE AF: 0.0105

Gnomad4 OTH AF: 0.0219

Alfa AF: 0.00166 Hom.: 1

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

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;