8-99136740-A-T

Position:

• chr8-99136740-A-T

Variant summary

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

The ENST00000357162.7(VPS13B):​c.1639A>T​(p.Thr547Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T547A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS13B ENST00000357162.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.84

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=0.07850006).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13B	NM_017890.5	c.1639A>T	p.Thr547Ser	missense_variant	12/62	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5	c.1639A>T	p.Thr547Ser	missense_variant	12/62	ENST00000357162.7	NP_689777.3
VPS13B	NM_015243.3	c.1639A>T	p.Thr547Ser	missense_variant	12/18		NP_056058.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7	c.1639A>T	p.Thr547Ser	missense_variant	12/62	1	NM_017890.5	ENSP00000351346
VPS13B	ENST00000357162.7	c.1639A>T	p.Thr547Ser	missense_variant	12/62	1	NM_152564.5	ENSP00000349685	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cohen syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 547 of the VPS13B protein (p.Thr547Ser). 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: 1437938). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt VPS13B protein function. 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	0.077
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	13
DANN	Benign	0.63
DEOGEN2	Benign	0.044	.;.;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.079	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.29	N;N;N
MutationTaster	Benign	0.90	N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.64	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.99	T;T;T
Sift4G	Benign	0.56	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.30
MutPred		0.12		Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		0.62
MPC		0.11
ClinPred		0.091	T
GERP RS		2.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.0
Varity_R		0.045
gMVP		0.13

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-100148968;