Genetic Variant VPS35:c.*283_*284delCA (chr16-46660187-TTG-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_018206.6(VPS35):c.*283_*284delCA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 136,728 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000024 ( 0 hom., cov: 12)

Exomes 𝑓: 0.00028 ( 4 hom. )

Consequence

VPS35
NM_018206.6 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.433

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
VPS35	NM_018206.6 link	c.283_284delCA	3_prime_UTR_variant	Exon 17 of 17	ENST00000299138.12	NP_060676.2	Q96QK1
VPS35	XM_011523227.4 link	c.283_284delCA	3_prime_UTR_variant	Exon 17 of 17		XP_011521529.1
VPS35	XM_005256045.4 link	c.283_284delCA	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.283_284delCA		3_prime_UTR_variant	Exon 17 of 17	1	NM_018206.6	ENSP00000299138.7		Q96QK1

Frequencies

GnomAD3 genomes

AF:

0.0000240

AC:

AN:

83502

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000423

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000249

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000282

AC:

AN:

53226

Hom.:

AF XY:

0.000112

AC XY:

AN XY:

26722

show subpopulations

Gnomad4 AFR exome

AF:

0.000420

AC:

AN:

2382

Gnomad4 AMR exome

AF:

0.00131

AC:

AN:

2284

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

2110

Gnomad4 EAS exome

AF:

0.000558

AC:

AN:

3586

Gnomad4 SAS exome

AF:

0.00130

AC:

AN:

1540

Gnomad4 FIN exome

AF:

0.000406

AC:

AN:

2466

Gnomad4 NFE exome

AF:

0.000172

AC:

AN:

34968

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

3630

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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:

0.0000240

AC:

AN:

83502

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

39990

show subpopulations

Gnomad4 AFR

AF:

0.0000423

AC:

0.0000423048

AN:

0.0000423048

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000249

AC:

0.0000249327

AN:

0.0000249327

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

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

Alfa

AF:

0.00

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

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

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