16-46660193-T-TTTG

Variant names:

• chr16-46660193-T-TTTG
• rs575317929
• NM_018206.6:c.*278_*279insCAA

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 0 publications found

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]

VPS35 Gene-Disease associations (from GenCC):

• Parkinson disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Parkinson disease 17

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• hereditary late onset Parkinson disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual disability

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 77 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018206.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS35	NM_018206.6	MANE Select	c.*278_*279insCAA		3_prime_UTR	Exon 17 of 17	NP_060676.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS35	ENST00000299138.12	TSL:1 MANE Select	c.*278_*279insCAA		3_prime_UTR	Exon 17 of 17	ENSP00000299138.7	Q96QK1
	VPS35	ENST00000568784.6	TSL:1	n.*3339_*3340insCAA		non_coding_transcript_exon	Exon 17 of 17	ENSP00000456274.2	H3BRJ7
	VPS35	ENST00000568784.6	TSL:1	n.*3339_*3340insCAA		3_prime_UTR	Exon 17 of 17	ENSP00000456274.2	H3BRJ7

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

African (AFR) AF: 0.00123 AC: 2 AN: 1628

American (AMR) AF: 0.00664 AC: 12 AN: 1808

Ashkenazi Jewish (ASJ) AF: 0.00487 AC: 9 AN: 1848

East Asian (EAS) AF: 0.000555 AC: 2 AN: 3604

South Asian (SAS) AF: 0.00738 AC: 8 AN: 1084

European-Finnish (FIN) AF: 0.00502 AC: 11 AN: 2190

Middle Eastern (MID) AF: 0.00917 AC: 2 AN: 218

European-Non Finnish (NFE) AF: 0.00418 AC: 124 AN: 29686

Other (OTH) AF: 0.00320 AC: 10 AN: 3126

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

African (AFR) AF: 0.00429 AC: 170 AN: 39650

American (AMR) AF: 0.0175 AC: 252 AN: 14392

Ashkenazi Jewish (ASJ) AF: 0.0188 AC: 64 AN: 3396

East Asian (EAS) AF: 0.00 AC: 0 AN: 4996

South Asian (SAS) AF: 0.00419 AC: 19 AN: 4538

European-Finnish (FIN) AF: 0.0245 AC: 206 AN: 8392

Middle Eastern (MID) AF: 0.0105 AC: 3 AN: 286

European-Non Finnish (NFE) AF: 0.0244 AC: 1608 AN: 65862

Other (OTH) AF: 0.0196 AC: 38 AN: 1938

Alfa AF: 0.0135 Hom.: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Parkinson Disease, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.35
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs575317929; hg19: chr16-46694105;