8-99013823-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_017890.5(VPS13B):c.35G>A(p.Ser12Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S12S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS13B NM_017890.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.62

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.

• 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5	c.35G>A	p.Ser12Asn	missense_variant	2/62	ENST00000358544.7
VPS13B	NM_152564.5	c.35G>A	p.Ser12Asn	missense_variant	2/62	ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000358544.7	c.35G>A	p.Ser12Asn	missense_variant	2/62	1	NM_017890.5
VPS13B	ENST00000357162.7	c.35G>A	p.Ser12Asn	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

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2023

The c.35G>A (p.S12N) alteration is located in exon 2 (coding exon 1) of the VPS13B gene. This alteration results from a G to A substitution at nucleotide position 35, causing the serine (S) at amino acid position 12 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
Cadd	Pathogenic	29
Dann	Uncertain	0.99
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.57	D;D;D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.2	L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Uncertain	0.44
Sift	Uncertain	0.0050	D;D;D;T
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.99	D;D;D;B
Vest4		0.72
MutPred		0.37		Gain of MoRF binding (P = 0.2786);Gain of MoRF binding (P = 0.2786);Gain of MoRF binding (P = 0.2786);Gain of MoRF binding (P = 0.2786);
MVP		0.79
MPC		0.30
ClinPred		0.97	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.46

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: chr8-100026051;