16-46660193-T-TTTG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_018206.6(VPS35):c.*278_*279insCAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 189,544 control chromosomes in the GnomAD database, including 120 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.016 (77 hom., cov: 29)
  • Exomes 𝑓: 0.0040 (43 hom.)
• Consequence: VPS35 NM_018206.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.351

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 -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0164 (2373/144352) while in subpopulation NFE AF= 0.0244 (1608/65862). AF 95% confidence interval is 0.0234. There are 77 homozygotes in gnomad4. There are 1107 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 2375 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS35	NM_018206.6	c.*278_*279insCAA		3_prime_UTR_variant	17/17	ENST00000299138.12
VPS35	XM_005256045.4	c.*278_*279insCAA		3_prime_UTR_variant	15/15
VPS35	XM_011523227.4	c.*278_*279insCAA		3_prime_UTR_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS35	ENST00000299138.12	c.*278_*279insCAA		3_prime_UTR_variant	17/17	1	NM_018206.6	P1
VPS35	ENST00000568784.6	c.*3339_*3340insCAA		3_prime_UTR_variant, NMD_transcript_variant	17/17	1
VPS35	ENST00000647959.1	c.*2732_*2733insCAA		3_prime_UTR_variant, NMD_transcript_variant	18/18

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2375 AN: 144254 Hom.: 77 Cov.: 29

Gnomad AFR AF: 0.00430

Gnomad AMI AF: 0.0144

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.0188

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00418

Gnomad FIN AF: 0.0245

Gnomad MID AF: 0.0129

Gnomad NFE AF: 0.0244

Gnomad OTH AF: 0.0198

GnomAD4 exome AF: 0.00398 AC: 180 AN: 45192 Hom.: 43 Cov.: 0 AF XY: 0.00298 AC XY: 69 AN XY: 23180

Gnomad4 AFR exome AF: 0.00123

Gnomad4 AMR exome AF: 0.00664

Gnomad4 ASJ exome AF: 0.00487

Gnomad4 EAS exome AF: 0.000555

Gnomad4 SAS exome AF: 0.00738

Gnomad4 FIN exome AF: 0.00502

Gnomad4 NFE exome AF: 0.00418

Gnomad4 OTH exome AF: 0.00320

GnomAD4 genome AF: 0.0164 AC: 2373 AN: 144352 Hom.: 77 Cov.: 29 AF XY: 0.0158 AC XY: 1107 AN XY: 70086

Gnomad4 AFR AF: 0.00429

Gnomad4 AMR AF: 0.0175

Gnomad4 ASJ AF: 0.0188

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00419

Gnomad4 FIN AF: 0.0245

Gnomad4 NFE AF: 0.0244

Gnomad4 OTH AF: 0.0196

Alfa AF: 0.0135 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

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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: rs575317929; hg19: chr16-46694105;