rs567003932

Variant names:

• chr8-99481759-C-T
• rs567003932
• NM_017890.5:c.3827C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-99481759-C-T
• chr8-99481759-C-A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_152564.5(VPS13B):​c.3827C>T​(p.Thr1276Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000173 in 1,613,926 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1276A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (4 hom.)
• Consequence: VPS13B NM_152564.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 4.47
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Cohen syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010489583).
• BP6: Variant 8-99481759-C-T is Benign according to our data. Variant chr8-99481759-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 528861.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152564.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	NM_017890.5	MANE Plus Clinical	c.3827C>T	p.Thr1276Ile	missense	Exon 25 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.3827C>T	p.Thr1276Ile	missense	Exon 25 of 62	NP_689777.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	ENST00000358544.7	TSL:1 MANE Plus Clinical	c.3827C>T	p.Thr1276Ile	missense	Exon 25 of 62	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.3827C>T	p.Thr1276Ile	missense	Exon 25 of 62	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000355155.6	TSL:1	n.3824C>T		non_coding_transcript_exon	Exon 25 of 28	ENSP00000347281.2	A0A8C8KE22

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000350 AC: 88 AN: 251082 AF XY: 0.000450

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000179 AC: 262 AN: 1461674 Hom.: 4 Cov.: 31 AF XY: 0.000252 AC XY: 183 AN XY: 727144

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00272 AC: 235 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111848

Other (OTH) AF: 0.000331 AC: 20 AN: 60386

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74434

African (AFR) AF: 0.0000241 AC: 1 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000673 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.000329 AC: 40

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Cohen syndrome (1)
-	-	1	VPS13B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	2.0	M
PhyloP100		4.5
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.12
Sift	Benign	0.15	T
Sift4G	Uncertain	0.019	D
Polyphen		0.93	P
Vest4		0.23
MutPred		0.11		Loss of phosphorylation at T1276 (P = 0.0025)
MVP		0.68
MPC		0.14
ClinPred		0.19	T
GERP RS		4.2
Varity_R		0.15
gMVP		0.39
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs567003932; hg19: chr8-100493987;