8-99121222-A-T

Position:

• chr8-99121222-A-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.983A>T​(p.His328Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,196 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. H328R) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.000013 (1 hom., cov: 32)
• Consequence: VPS13B NM_152564.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.64

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]

VPS13B (HGNC:):

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=0.13319635).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13B	NM_017890.5	c.983A>T	p.His328Leu	missense_variant	8/62	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5	c.983A>T	p.His328Leu	missense_variant	8/62	ENST00000357162.7	NP_689777.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7	c.983A>T	p.His328Leu	missense_variant	8/62	1	NM_017890.5	ENSP00000351346.2
VPS13B	ENST00000357162.7	c.983A>T	p.His328Leu	missense_variant	8/62	1	NM_152564.5	ENSP00000349685.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152196 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152196 Hom.: 1 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.074	.;.;T;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.66	T;T;T;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.34	N;N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.56	T;T;T;T
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.41
MutPred		0.25		Loss of disorder (P = 0.0436);Loss of disorder (P = 0.0436);Loss of disorder (P = 0.0436);Loss of disorder (P = 0.0436);
MVP		0.70
MPC		0.15
ClinPred		0.38	T
GERP RS		4.5
Varity_R		0.086
gMVP		0.40

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: rs181625846; hg19: chr8-100133450;