8-99853454-G-T

Position:

chr8-99853454-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_152564.5(VPS13B):c.10065G>T(p.Ala3355Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 1,614,024 control chromosomes in the GnomAD database, including 430 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 23 hom., cov: 32)

Exomes 𝑓: 0.022 ( 407 hom. )

Consequence

VPS13B
NM_152564.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.231

Variant links:

Genes affected

VPS13B (HGNC:2183): (vacuolar protein sorting 13 homolog B) This gene encodes a potential transmembrane protein that may function in vesicle-mediated transport and sorting of proteins within the cell. This protein may play a role in the development and the function of the eye, hematological system, and central nervous system. Mutations in this gene have been associated with Cohen syndrome. Multiple splice variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

VPS13B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 8-99853454-G-T is Benign according to our data. Variant chr8-99853454-G-T is described in ClinVar as [Benign]. Clinvar id is 459245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-99853454-G-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.231 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0173 (2634/152290) while in subpopulation NFE AF= 0.0258 (1756/68018). AF 95% confidence interval is 0.0248. There are 23 homozygotes in gnomad4. There are 1225 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13B	NM_017890.5 link	c.10140G>T	p.Ala3380Ala	synonymous_variant	56/62	ENST00000358544.7	NP_060360.3	Q7Z7G8-1
VPS13B	NM_152564.5 link	c.10065G>T	p.Ala3355Ala	synonymous_variant	56/62	ENST00000357162.7	NP_689777.3	Q7Z7G8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7 link	c.10140G>T	p.Ala3380Ala	synonymous_variant	56/62	1	NM_017890.5	ENSP00000351346.2		Q7Z7G8-1
VPS13B	ENST00000357162.7 link	c.10065G>T	p.Ala3355Ala	synonymous_variant	56/62	1	NM_152564.5	ENSP00000349685.2		Q7Z7G8-2

Frequencies

GnomAD3 genomes

AF:

0.0173

AC:

2635

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00555

Gnomad AMI

AF:

0.0658

Gnomad AMR

AF:

0.0194

Gnomad ASJ

AF:

0.0248

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00725

Gnomad FIN

AF:

0.00970

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0258

Gnomad OTH

AF:

0.0277

GnomAD3 exomes

AF:

0.0174

AC:

4356

AN:

250630

Hom.:

AF XY:

0.0181

AC XY:

2454

AN XY:

135560

show subpopulations

Gnomad AFR exome

AF:

0.00492

Gnomad AMR exome

AF:

0.0148

Gnomad ASJ exome

AF:

0.0222

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00699

Gnomad FIN exome

AF:

0.00989

Gnomad NFE exome

AF:

0.0260

Gnomad OTH exome

AF:

0.0282

GnomAD4 exome

AF:

0.0224

AC:

32788

AN:

1461734

Hom.:

407

Cov.:

AF XY:

0.0221

AC XY:

16041

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.00427

Gnomad4 AMR exome

AF:

0.0148

Gnomad4 ASJ exome

AF:

0.0235

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00698

Gnomad4 FIN exome

AF:

0.0119

Gnomad4 NFE exome

AF:

0.0258

Gnomad4 OTH exome

AF:

0.0217

GnomAD4 genome

AF:

0.0173

AC:

2634

AN:

152290

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

1225

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00553

Gnomad4 AMR

AF:

0.0194

Gnomad4 ASJ

AF:

0.0248

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00726

Gnomad4 FIN

AF:

0.00970

Gnomad4 NFE

AF:

0.0258

Gnomad4 OTH

AF:

0.0274

Alfa

AF:

0.0148

Hom.:

Bravo

AF:

0.0176

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0298

EpiControl

AF:

0.0278

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cohen syndrome

Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 19, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 10, 2022

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.037

DANN

Benign

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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