Variant 16-19669298-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The ENST00000417362.7(VPS35L):c.2360C>T(p.Pro787Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000162 in 1,606,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

VPS35L
ENST00000417362.7 missense, splice_region

Scores

Splicing: ADA: 0.9981

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.85

Variant links:

Genes affected

VPS35L (HGNC:24641): (VPS35 endosomal protein sorting factor like) Involved in Golgi to plasma membrane transport and endocytic recycling. Located in endosome. Implicated in Ritscher-Schinzel syndrome. [provided by Alliance of Genome Resources, Apr 2022]

VPS35L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.922

PP5

Variant 16-19669298-C-T is Pathogenic according to our data. Variant chr16-19669298-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3068429.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS35L	NM_020314.7 linkuse as main transcript	c.2360C>T	p.Pro787Leu	missense_variant, splice_region_variant	27/31	ENST00000417362.7	NP_064710.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS35L	ENST00000417362.7 linkuse as main transcript	c.2360C>T	p.Pro787Leu	missense_variant, splice_region_variant	27/31	1	NM_020314.7	ENSP00000395973	P1	Q7Z3J2-1
VPS35L	ENST00000251143.9 linkuse as main transcript	c.2627C>T	p.Pro876Leu	missense_variant, splice_region_variant	27/31	1		ENSP00000251143
VPS35L	ENST00000543152.5 linkuse as main transcript	c.1607C>T	p.Pro536Leu	missense_variant, splice_region_variant	21/25	1		ENSP00000457973
VPS35L	ENST00000542263.5 linkuse as main transcript	c.2081C>T	p.Pro694Leu	missense_variant, splice_region_variant	24/28	2		ENSP00000442468

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000439

AC:

AN:

250406

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135384

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000165

AC:

AN:

1454430

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

722776

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000127

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000195

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Ritscher-Schinzel syndrome 3

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.47

T;T;.;.;.;T

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

.;D;D;D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.92

D;D;D;D;D;D

MetaSVM

Uncertain

-0.15

MutationTaster

Benign

1.0

D;D;D;D;D;D

PROVEAN

Pathogenic

-9.3

D;.;D;.;D;D

REVEL

Uncertain

0.53

Sift

Uncertain

0.0020

D;.;D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

0.99

.;.;D;.;.;.

Vest4

0.98

MutPred

0.79

.;.;.;Gain of sheet (P = 0.1539);.;.;

MVP

0.72

MPC

0.72

ClinPred

0.90

GERP RS

5.5

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

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