rs168745

Positions:

• chr16-46662372-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_018206.6(VPS35):​c.1938C>T​(p.His646=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.996 in 1,614,194 control chromosomes in the GnomAD database, including 800,376 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.98 (72733 hom., cov: 32)
  • Exomes 𝑓: 1.0 (727643 hom.)
• Consequence: VPS35 NM_018206.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:4
• Conservation: PhyloP100: 0.341

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 16-46662372-G-A is Benign according to our data. Variant chr16-46662372-G-A is described in ClinVar as [Benign]. Clinvar id is 1166780.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-46662372-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.341 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS35	NM_018206.6	c.1938C>T	p.His646=	synonymous_variant	15/17	ENST00000299138.12
VPS35	XM_011523227.4	c.1851C>T	p.His617=	synonymous_variant	15/17
VPS35	XM_005256045.4	c.1737C>T	p.His579=	synonymous_variant	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS35	ENST00000299138.12	c.1938C>T	p.His646=	synonymous_variant	15/17	1	NM_018206.6	P1
VPS35	ENST00000568784.6	c.*2608C>T		3_prime_UTR_variant, NMD_transcript_variant	15/17	1
VPS35	ENST00000562420.1	n.576C>T		non_coding_transcript_exon_variant	3/4	2
VPS35	ENST00000647959.1	c.*2001C>T		3_prime_UTR_variant, NMD_transcript_variant	16/18

Frequencies

GnomAD3 genomes AF: 0.977 AC: 148661 AN: 152186 Hom.: 72688 Cov.: 32

Gnomad AFR AF: 0.919

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.992

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.982

GnomAD3 exomes AF: 0.994 AC: 249749 AN: 251282 Hom.: 124151 AF XY: 0.996 AC XY: 135216 AN XY: 135796

Gnomad AFR exome AF: 0.917

Gnomad AMR exome AF: 0.996

Gnomad ASJ exome AF: 0.999

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.998 AC: 1458489 AN: 1461890 Hom.: 727643 Cov.: 76 AF XY: 0.998 AC XY: 725836 AN XY: 727244

Gnomad4 AFR exome AF: 0.917

Gnomad4 AMR exome AF: 0.995

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.995

GnomAD4 genome AF: 0.977 AC: 148763 AN: 152304 Hom.: 72733 Cov.: 32 AF XY: 0.977 AC XY: 72764 AN XY: 74478

Gnomad4 AFR AF: 0.919

Gnomad4 AMR AF: 0.992

Gnomad4 ASJ AF: 0.999

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.982

Alfa AF: 0.989 Hom.: 38268

Bravo AF: 0.973

Asia WGS AF: 0.997 AC: 3466 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Parkinson disease 17 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	3.5
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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

Other links and lift over

dbSNP: rs168745; hg19: chr16-46696284;