8-99013819-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_017890.5(VPS13B):c.31A>T(p.Met11Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS13B NM_017890.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.88

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 2 ACMG points.

• PM1: In a domain Chorein N-terminal (size 100) in uniprot entity VP13B_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_017890.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19959974).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5	c.31A>T	p.Met11Leu	missense_variant	2/62	ENST00000358544.7
VPS13B	NM_152564.5	c.31A>T	p.Met11Leu	missense_variant	2/62	ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000358544.7	c.31A>T	p.Met11Leu	missense_variant	2/62	1	NM_017890.5
VPS13B	ENST00000357162.7	c.31A>T	p.Met11Leu	missense_variant	2/62	1	NM_152564.5	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

Invitae

Jun 14, 2022

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 11 of the VPS13B protein (p.Met11Leu). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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	Uncertain	0.36
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	23
Dann	Benign	0.94
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.41	N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.64	N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.97	T;T;T;T
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.12	B;P;B;B
Vest4		0.43
MutPred		0.52		Loss of disorder (P = 0.2162);Loss of disorder (P = 0.2162);Loss of disorder (P = 0.2162);Loss of disorder (P = 0.2162);
MVP		0.46
MPC		0.11
ClinPred		0.76	D
GERP RS		2.4
Varity_R		0.11
gMVP		0.49

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: chr8-100026047;