chr8-99556578-G-T

Variant names:

• chr8-99556578-G-T
• rs1014154776
• NM_017890.5:c.4949G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152564.5(VPS13B):​c.4874G>T​(p.Ser1625Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VPS13B NM_152564.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.736

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07785669).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13B	NM_017890.5	c.4949G>T	p.Ser1650Ile	missense_variant	Exon 31 of 62	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5	c.4874G>T	p.Ser1625Ile	missense_variant	Exon 31 of 62	ENST00000357162.7	NP_689777.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7	c.4949G>T	p.Ser1650Ile	missense_variant	Exon 31 of 62	1	NM_017890.5	ENSP00000351346.2
VPS13B	ENST00000357162.7	c.4874G>T	p.Ser1625Ile	missense_variant	Exon 31 of 62	1	NM_152564.5	ENSP00000349685.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250592 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135402

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.000164

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461006 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726810

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Oct 22, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

VPS13B-related disorder Uncertain:1

Sep 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The VPS13B c.4874G>T variant is predicted to result in the amino acid substitution p.Ser1625Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported on 1 allele in the 'remaining individuals' cohort in gnomAD (1 of ~250,000 alleles in the gnomAD database). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cohen syndrome Uncertain:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1650 of the VPS13B protein (p.Ser1650Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with VPS13B-related conditions. ClinVar contains an entry for this variant (Variation ID: 437256). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt VPS13B protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.076	.;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.078	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.1	.;L
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.034
Sift	Benign	0.038	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.37	B;B
Vest4		0.18
MutPred		0.35		.;Loss of disorder (P = 0.0149);
MVP		0.42
MPC		0.17
ClinPred		0.26	T
GERP RS		1.5
Varity_R		0.071
gMVP		0.31

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: rs1014154776; hg19: chr8-100568806;