Variant 16-19629820-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The ENST00000417362.7(VPS35L):c.1554G>A(p.Thr518=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00324 in 1,612,860 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0022 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0033 ( 16 hom. )

Consequence

VPS35L
ENST00000417362.7 splice_region, synonymous

Scores

Splicing: ADA: 0.9991

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.09

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 Benign. Variant got -12 ACMG points.

BP6

Variant 16-19629820-G-A is Benign according to our data. Variant chr16-19629820-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2672622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS35L	NM_020314.7 linkuse as main transcript	c.1554G>A	p.Thr518=	splice_region_variant, synonymous_variant	18/31	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.1554G>A	p.Thr518=	splice_region_variant, synonymous_variant	18/31	1	NM_020314.7	ENSP00000395973	P1	Q7Z3J2-1
VPS35L	ENST00000251143.9 linkuse as main transcript	c.1821G>A	p.Thr607=	splice_region_variant, synonymous_variant	18/31	1		ENSP00000251143
VPS35L	ENST00000543152.5 linkuse as main transcript	c.801G>A	p.Thr267=	splice_region_variant, synonymous_variant	12/25	1		ENSP00000457973
VPS35L	ENST00000542263.5 linkuse as main transcript	c.1353G>A	p.Thr451=	splice_region_variant, synonymous_variant	16/28	2		ENSP00000442468

Frequencies

GnomAD3 genomes

AF:

0.00218

AC:

331

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00255

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00362

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00243

AC:

612

AN:

251414

Hom.:

AF XY:

0.00222

AC XY:

301

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.000867

Gnomad ASJ exome

AF:

0.00476

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00296

Gnomad NFE exome

AF:

0.00372

Gnomad OTH exome

AF:

0.00408

GnomAD4 exome

AF:

0.00335

AC:

4891

AN:

1460618

Hom.:

Cov.:

AF XY:

0.00326

AC XY:

2366

AN XY:

726732

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.000939

Gnomad4 ASJ exome

AF:

0.00566

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000417

Gnomad4 FIN exome

AF:

0.00290

Gnomad4 NFE exome

AF:

0.00388

Gnomad4 OTH exome

AF:

0.00298

GnomAD4 genome

AF:

0.00217

AC:

331

AN:

152242

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

150

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.000698

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00255

Gnomad4 NFE

AF:

0.00362

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00339

Hom.:

Bravo

AF:

0.00218

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00442

EpiControl

AF:

0.00344

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

VPS35L-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 19, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Ritscher-Schinzel syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Jun 06, 2023

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

VPS35L: PP3, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.89

SpliceAI score (max)

0.64

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.64

Position offset: 15

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