16-46660192-T-TTTTG

Position:

• chr16-46660192-T-TTTTG

Variant summary

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

The NM_018206.6(VPS35):​c.*279_*280insCAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000388 in 175,294 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00095 (7 hom.)
• Consequence: VPS35 NM_018206.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.370

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 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS35	NM_018206.6	c.*279_*280insCAAA		3_prime_UTR_variant	17/17	ENST00000299138.12	NP_060676.2
VPS35	XM_005256045.4	c.*279_*280insCAAA		3_prime_UTR_variant	15/15		XP_005256102.1
VPS35	XM_011523227.4	c.*279_*280insCAAA		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.*279_*280insCAAA		3_prime_UTR_variant	17/17	1	NM_018206.6	ENSP00000299138	P1
VPS35	ENST00000568784.6	c.*3340_*3341insCAAA		3_prime_UTR_variant, NMD_transcript_variant	17/17	1		ENSP00000456274
VPS35	ENST00000647959.1	c.*2733_*2734insCAAA		3_prime_UTR_variant, NMD_transcript_variant	18/18			ENSP00000497702

Frequencies

GnomAD3 genomes AF: 0.000211 AC: 28 AN: 132896 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000518

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000319

Gnomad EAS AF: 0.000679

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000945 AC: 40 AN: 42318 Hom.: 7 Cov.: 0 AF XY: 0.000827 AC XY: 18 AN XY: 21764

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00288

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00191

Gnomad4 FIN exome AF: 0.000963

Gnomad4 NFE exome AF: 0.000937

Gnomad4 OTH exome AF: 0.000684

GnomAD4 genome AF: 0.000211 AC: 28 AN: 132976 Hom.: 0 Cov.: 29 AF XY: 0.000155 AC XY: 10 AN XY: 64322

Gnomad4 AFR AF: 0.0000517

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000319

Gnomad4 EAS AF: 0.000681

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000367

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

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: rs886052006; hg19: chr16-46694104;