rs148788159

Variant names:

• chr8-99193015-G-A
• rs148788159
• NM_017890.5:c.2473G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-99193015-G-A
• chr8-99193015-G-C
• chr8-99193015-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_152564.5(VPS13B):​c.2473G>A​(p.Ala825Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000936 in 1,613,664 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A825V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000097 (1 hom.)
• Consequence: VPS13B NM_152564.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:11
• Conservation: PhyloP100: 1.11
• Publications: 6 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031285197).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000972 (142/1461426) while in subpopulation MID AF = 0.00607 (35/5762). AF 95% confidence interval is 0.00449. There are 1 homozygotes in GnomAdExome4. There are 62 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.2473G>A	p.Ala825Thr	missense	Exon 17 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.2473G>A	p.Ala825Thr	missense	Exon 17 of 62	NP_689777.3
	VPS13B	NM_015243.3		c.2473G>A	p.Ala825Thr	missense	Exon 17 of 18	NP_056058.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	ENST00000358544.7	TSL:1 MANE Plus Clinical	c.2473G>A	p.Ala825Thr	missense	Exon 17 of 62	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.2473G>A	p.Ala825Thr	missense	Exon 17 of 62	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000355155.6	TSL:1	n.2473G>A		non_coding_transcript_exon	Exon 17 of 28	ENSP00000347281.2	A0A8C8KE22

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000111 AC: 28 AN: 251168 AF XY: 0.0000884

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000972 AC: 142 AN: 1461426 Hom.: 1 Cov.: 31 AF XY: 0.0000853 AC XY: 62 AN XY: 727016

African (AFR) AF: 0.000149 AC: 5 AN: 33466

American (AMR) AF: 0.0000894 AC: 4 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86246

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53300

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5762

European-Non Finnish (NFE) AF: 0.0000675 AC: 75 AN: 1111822

Other (OTH) AF: 0.000199 AC: 12 AN: 60376

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74436

African (AFR) AF: 0.0000481 AC: 2 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67994

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000140 AC: 17

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	5	-	Cohen syndrome (5)
-	3	-	not provided (3)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)
-	1	-	VPS13B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.0
DANN	Benign	0.53
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.34	N
PhyloP100		1.1
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.047
Sift	Benign	0.45	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.068
MVP		0.54
MPC		0.12
ClinPred		0.0025	T
GERP RS		0.83
Varity_R		0.025
gMVP		0.22
Mutation Taster		=96/4	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: rs148788159; hg19: chr8-100205243; COSMIC: COSV62021131;