rs138127778

Positions:

• chr8-99848882-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_017890.5(VPS13B):​c.10124C>T​(p.Thr3375Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00855 in 1,613,934 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0087 (66 hom.)
• Consequence: VPS13B NM_017890.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.02

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004468918).
• BP6: Variant 8-99848882-C-T is Benign according to our data. Variant chr8-99848882-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 130717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-99848882-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13B	NM_017890.5	c.10124C>T	p.Thr3375Ile	missense_variant	55/62	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5	c.10049C>T	p.Thr3350Ile	missense_variant	55/62	ENST00000357162.7	NP_689777.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7	c.10124C>T	p.Thr3375Ile	missense_variant	55/62	1	NM_017890.5	ENSP00000351346
VPS13B	ENST00000357162.7	c.10049C>T	p.Thr3350Ile	missense_variant	55/62	1	NM_152564.5	ENSP00000349685	P1

Frequencies

GnomAD3 genomes AF: 0.00666 AC: 1013 AN: 152204 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00819

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00965

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00801 AC: 2015 AN: 251428 Hom.: 8 AF XY: 0.00882 AC XY: 1199 AN XY: 135886

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00708

Gnomad ASJ exome AF: 0.0174

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0111

Gnomad FIN exome AF: 0.00360

Gnomad NFE exome AF: 0.00959

Gnomad OTH exome AF: 0.00978

GnomAD4 exome AF: 0.00875 AC: 12785 AN: 1461612 Hom.: 66 Cov.: 31 AF XY: 0.00902 AC XY: 6558 AN XY: 727118

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.00704

Gnomad4 ASJ exome AF: 0.0160

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0113

Gnomad4 FIN exome AF: 0.00348

Gnomad4 NFE exome AF: 0.00922

Gnomad4 OTH exome AF: 0.00863

GnomAD4 genome AF: 0.00663 AC: 1010 AN: 152322 Hom.: 6 Cov.: 32 AF XY: 0.00667 AC XY: 497 AN XY: 74484

Gnomad4 AFR AF: 0.00178

Gnomad4 AMR AF: 0.00811

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00973

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.00966

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00924 Hom.: 9

Bravo AF: 0.00672

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0112 AC: 96

ExAC AF: 0.00810 AC: 984

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0114

EpiControl AF: 0.0122

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 15, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	VPS13B: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2019	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Cohen syndrome Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 17, 2019	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 27, 2014	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2017

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
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.43
DANN	Benign	0.85
DEOGEN2	Benign	0.11	.;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.69	T;T
MetaRNN	Benign	0.0045	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.3	.;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.099
Sift	Benign	0.21	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.0010	B;B
Vest4		0.17
MVP		0.60
MPC		0.13
ClinPred		0.0038	T
GERP RS		3.9
Varity_R		0.043
gMVP		0.24

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: rs138127778; hg19: chr8-100861110;