8-99835268-G-T

Position:

• chr8-99835268-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_017890.5(VPS13B):​c.9761G>T​(p.Arg3254Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3254Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: VPS13B NM_017890.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.97

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5	c.9761G>T	p.Arg3254Leu	missense_variant	53/62	ENST00000358544.7
VPS13B	NM_152564.5	c.9686G>T	p.Arg3229Leu	missense_variant	53/62	ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000358544.7	c.9761G>T	p.Arg3254Leu	missense_variant	53/62	1	NM_017890.5
VPS13B	ENST00000357162.7	c.9686G>T	p.Arg3229Leu	missense_variant	53/62	1	NM_152564.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251022 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135672

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: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461496 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727078

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: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	.;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	-0.034	T
MutationAssessor	Uncertain	2.4	.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0070	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.94	P;D
Vest4		0.86
MutPred		0.40		.;Gain of sheet (P = 0.0344);
MVP		0.92
MPC		0.25
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.29
gMVP		0.85

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: rs769856598; hg19: chr8-100847496;