16-46659709-C-CAA

Variant summary

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

The NM_018206.6(VPS35):c.*762_*763insTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 143,360 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0 (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: 2.88

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd at 19 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000133 AC: 19 AN: 143292 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000205

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00158

Gnomad SAS AF: 0.000218

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000107

Gnomad OTH AF: 0.00

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: 0.000146 AC: 21 AN: 143360 Hom.: 0 Cov.: 30 AF XY: 0.000158 AC XY: 11 AN XY: 69544

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000342

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00158

Gnomad4 SAS AF: 0.000219

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000107

Gnomad4 OTH AF: 0.00

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: rs34926621; hg19: chr16-46693621;