16-46660188-TG-T

Position:

• chr16-46660188-TG-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_018206.6(VPS35):​c.*283del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.090 (487 hom., cov: 12)
  • Exomes 𝑓: 0.0080 (42 hom.)
• Consequence: VPS35 NM_018206.6 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.865

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 -9 ACMG points.

• BP6: Variant 16-46660188-TG-T is Benign according to our data. Variant chr16-46660188-TG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 319278.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS35	NM_018206.6	c.*283del		3_prime_UTR_variant	17/17	ENST00000299138.12	NP_060676.2
VPS35	XM_005256045.4	c.*283del		3_prime_UTR_variant	15/15		XP_005256102.1
VPS35	XM_011523227.4	c.*283del		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.*283del		3_prime_UTR_variant	17/17	1	NM_018206.6	ENSP00000299138	P1
VPS35	ENST00000568784.6	c.*3344del		3_prime_UTR_variant, NMD_transcript_variant	17/17	1		ENSP00000456274
VPS35	ENST00000647959.1	c.*2737del		3_prime_UTR_variant, NMD_transcript_variant	18/18			ENSP00000497702

Frequencies

GnomAD3 genomes AF: 0.0897 AC: 7873 AN: 87780 Hom.: 487 Cov.: 12

Gnomad AFR AF: 0.0220

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.0625

Gnomad ASJ AF: 0.0952

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.409

Gnomad FIN AF: 0.0654

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.0983

GnomAD4 exome AF: 0.00800 AC: 375 AN: 46904 Hom.: 42 Cov.: 0 AF XY: 0.00953 AC XY: 227 AN XY: 23814

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00363

Gnomad4 ASJ exome AF: 0.00158

Gnomad4 EAS exome AF: 0.00187

Gnomad4 SAS exome AF: 0.152

Gnomad4 FIN exome AF: 0.00594

Gnomad4 NFE exome AF: 0.00496

Gnomad4 OTH exome AF: 0.00400

GnomAD4 genome AF: 0.0896 AC: 7871 AN: 87816 Hom.: 487 Cov.: 12 AF XY: 0.0915 AC XY: 3873 AN XY: 42318

Gnomad4 AFR AF: 0.0220

Gnomad4 AMR AF: 0.0622

Gnomad4 ASJ AF: 0.0952

Gnomad4 EAS AF: 0.108

Gnomad4 SAS AF: 0.412

Gnomad4 FIN AF: 0.0654

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.0970

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Parkinson Disease, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 02, 2019

- -

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: rs886052005; hg19: chr16-46694100;