Genetic Variant VPS35:c.*278_*279insCAA (chr16-46660193-T-TTTG) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

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

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.351

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 2373 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
VPS35	NM_018206.6 link	c.278_279insCAA	3_prime_UTR_variant	Exon 17 of 17	ENST00000299138.12	NP_060676.2	Q96QK1
VPS35	XM_011523227.4 link	c.278_279insCAA	3_prime_UTR_variant	Exon 17 of 17		XP_011521529.1
VPS35	XM_005256045.4 link	c.278_279insCAA	3_prime_UTR_variant	Exon 15 of 15		XP_005256102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS35	ENST00000299138 link	c.278_279insCAA		3_prime_UTR_variant	Exon 17 of 17	1	NM_018206.6	ENSP00000299138.7		Q96QK1

Frequencies

GnomAD3 genomes

AF:

0.0165

AC:

2375

AN:

144254

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.00298

AC XY:

AN XY:

23180

show subpopulations

Gnomad4 AFR exome

AF:

0.00123

AC:

AN:

1628

Gnomad4 AMR exome

AF:

0.00664

AC:

AN:

1808

Gnomad4 ASJ exome

AF:

0.00487

AC:

AN:

1848

Gnomad4 EAS exome

AF:

0.000555

AC:

AN:

3604

Gnomad4 SAS exome

AF:

0.00738

AC:

AN:

1084

Gnomad4 FIN exome

AF:

0.00502

AC:

AN:

2190

Gnomad4 NFE exome

AF:

0.00418

AC:

124

AN:

29686

Gnomad4 Remaining exome

AF:

0.00320

AC:

AN:

3126

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0164

AC:

2373

AN:

144352

Hom.:

Cov.:

AF XY:

0.0158

AC XY:

1107

AN XY:

70086

show subpopulations

Gnomad4 AFR

AF:

0.00429

AC:

0.00428752

AN:

0.00428752

Gnomad4 AMR

AF:

0.0175

AC:

0.0175097

AN:

0.0175097

Gnomad4 ASJ

AF:

0.0188

AC:

0.0188457

AN:

0.0188457

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00419

AC:

0.00418687

AN:

0.00418687

Gnomad4 FIN

AF:

0.0245

AC:

0.0245472

AN:

0.0245472

Gnomad4 NFE

AF:

0.0244

AC:

0.0244147

AN:

0.0244147

Gnomad4 OTH

AF:

0.0196

AC:

0.0196078

AN:

0.0196078

Heterozygous variant carriers

180

269

359

449

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0135

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Parkinson Disease, Dominant

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=100/0

polymorphism

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over