8-99871517-A-G

Variant names:

• chr8-99871517-A-G
• rs7844645
• NM_017890.5:c.11640A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_152564.5(VPS13B):​c.11565A>G​(p.Ser3855Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00587 in 1,614,200 control chromosomes in the GnomAD database, including 453 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S3855S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.032 (231 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (222 hom.)
• Consequence: VPS13B NM_152564.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.63
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 8-99871517-A-G is Benign according to our data. Variant chr8-99871517-A-G is described in ClinVar as Benign. ClinVar VariationId is 130721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.63 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

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.11640A>G	p.Ser3880Ser	synonymous	Exon 61 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.11565A>G	p.Ser3855Ser	synonymous	Exon 61 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.11640A>G	p.Ser3880Ser	synonymous	Exon 61 of 62	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.11565A>G	p.Ser3855Ser	synonymous	Exon 61 of 62	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000493587.1	TSL:2	n.1142A>G		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.0317 AC: 4821 AN: 152204 Hom.: 230 Cov.: 33

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0249

GnomAD2 exomes AF: 0.00828 AC: 2082 AN: 251458 AF XY: 0.00635

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.00619

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00318 AC: 4643 AN: 1461878 Hom.: 222 Cov.: 31 AF XY: 0.00274 AC XY: 1995 AN XY: 727242

African (AFR) AF: 0.111 AC: 3716 AN: 33480

American (AMR) AF: 0.00709 AC: 317 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5766

European-Non Finnish (NFE) AF: 0.000145 AC: 161 AN: 1112008

Other (OTH) AF: 0.00694 AC: 419 AN: 60394

GnomAD4 genome AF: 0.0317 AC: 4829 AN: 152322 Hom.: 231 Cov.: 33 AF XY: 0.0311 AC XY: 2316 AN XY: 74476

African (AFR) AF: 0.108 AC: 4475 AN: 41554

American (AMR) AF: 0.0172 AC: 263 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68030

Other (OTH) AF: 0.0246 AC: 52 AN: 2114

Alfa AF: 0.0159 Hom.: 82

Bravo AF: 0.0358

Asia WGS AF: 0.00722 AC: 26 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.41
DANN	Benign	0.75
PhyloP100		-1.6
Mutation Taster		=97/3	polymorphism (auto)

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: rs7844645; hg19: chr8-100883745;