rs587780497

Positions:

• chr8-99853867-A-G

Variant summary

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

The NM_017890.5(VPS13B):​c.10553A>G​(p.Asp3518Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 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: 6.8e-7 (0 hom.)
• Consequence: VPS13B NM_017890.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.47

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=0.16566297).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13B	NM_017890.5	c.10553A>G	p.Asp3518Gly	missense_variant	56/62	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5	c.10478A>G	p.Asp3493Gly	missense_variant	56/62	ENST00000357162.7	NP_689777.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7	c.10553A>G	p.Asp3518Gly	missense_variant	56/62	1	NM_017890.5	ENSP00000351346
VPS13B	ENST00000357162.7	c.10478A>G	p.Asp3493Gly	missense_variant	56/62	1	NM_152564.5	ENSP00000349685	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727246

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 12, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	16
DANN	Benign	0.60
DEOGEN2	Benign	0.067	.;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.6	.;L
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.66	N;N
REVEL	Benign	0.20
Sift	Benign	0.47	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.020	B;B
Vest4		0.38
MutPred		0.55		.;Loss of helix (P = 0.0558);
MVP		0.69
MPC		0.39
ClinPred		0.23	T
GERP RS		5.7
Varity_R		0.10
gMVP		0.53

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: rs587780497; hg19: chr8-100866095;