Genetic Variant VPS35L:p.Leu354Leu (chr16-19616152-A-C) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_020314.7(VPS35L):c.1062A>C(p.Leu354Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00537 in 1,613,634 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0047 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0054 ( 36 hom. )

Consequence

VPS35L
NM_020314.7 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.14

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 -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 16-19616152-A-C is Benign according to our data. Variant chr16-19616152-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2646277.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-1.14 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00472 (719/152174) while in subpopulation NFE AF= 0.00719 (489/68002). AF 95% confidence interval is 0.00666. There are 6 homozygotes in gnomad4. There are 338 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS35L	NM_020314.7 link	c.1062A>C	p.Leu354Leu	synonymous_variant	Exon 13 of 31	ENST00000417362.7	NP_064710.5	Q7Z3J2-1E7EWW0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS35L	ENST00000417362.7 link	c.1062A>C	p.Leu354Leu	synonymous_variant	Exon 13 of 31	1	NM_020314.7	ENSP00000395973.3		Q7Z3J2-1

Frequencies

GnomAD3 genomes

AF:

0.00475

AC:

722

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000870

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.00951

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00396

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.00720

Gnomad OTH

AF:

0.00909

GnomAD3 exomes

AF:

0.00537

AC:

1351

AN:

251452

Hom.:

AF XY:

0.00569

AC XY:

773

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00367

Gnomad ASJ exome

AF:

0.00655

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00379

Gnomad FIN exome

AF:

0.00379

Gnomad NFE exome

AF:

0.00803

Gnomad OTH exome

AF:

0.00554

GnomAD4 exome

AF:

0.00544

AC:

7946

AN:

1461460

Hom.:

Cov.:

AF XY:

0.00545

AC XY:

3965

AN XY:

727050

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.00371

Gnomad4 ASJ exome

AF:

0.00747

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00347

Gnomad4 FIN exome

AF:

0.00433

Gnomad4 NFE exome

AF:

0.00598

Gnomad4 OTH exome

AF:

0.00527

GnomAD4 genome

AF:

0.00472

AC:

719

AN:

152174

Hom.:

Cov.:

AF XY:

0.00454

AC XY:

338

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.000867

Gnomad4 AMR

AF:

0.00380

Gnomad4 ASJ

AF:

0.00951

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.00396

Gnomad4 NFE

AF:

0.00719

Gnomad4 OTH

AF:

0.00900

Alfa

AF:

0.00664

Hom.:

Bravo

AF:

0.00473

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00979

EpiControl

AF:

0.00824

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

VPS35L: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.96

DANN

Benign

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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