rs142476821

Variant names:

• chr8-99861802-G-A
• rs142476821
• NM_017890.5:c.11146G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-99861802-G-A
• chr8-99861802-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017890.5(VPS13B):​c.11146G>A​(p.Ala3716Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00549 in 1,597,778 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (36 hom.)
• Consequence: VPS13B NM_017890.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 9.20
• Publications: 14 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: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.037311763).
• BP6: Variant 8-99861802-G-A is Benign according to our data. Variant chr8-99861802-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00307 (468/152264) while in subpopulation NFE AF = 0.00548 (373/68016). AF 95% confidence interval is 0.00502. There are 3 homozygotes in GnomAd4. There are 209 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017890.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	NM_017890.5	MANE Plus Clinical	c.11146G>A	p.Ala3716Thr	missense	Exon 58 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.11071G>A	p.Ala3691Thr	missense	Exon 58 of 62	NP_689777.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	ENST00000358544.7	TSL:1 MANE Plus Clinical	c.11146G>A	p.Ala3716Thr	missense	Exon 58 of 62	ENSP00000351346.2
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.11071G>A	p.Ala3691Thr	missense	Exon 58 of 62	ENSP00000349685.2
	VPS13B	ENST00000682153.1		n.*240G>A		non_coding_transcript_exon	Exon 59 of 62	ENSP00000507923.1

Frequencies

GnomAD3 genomes AF: 0.00308 AC: 469 AN: 152146 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00550

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00246 AC: 547 AN: 221998 AF XY: 0.00264

Gnomad AFR exome AF: 0.00125

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000529

Gnomad NFE exome AF: 0.00448

Gnomad OTH exome AF: 0.00253

GnomAD4 exome AF: 0.00574 AC: 8298 AN: 1445514 Hom.: 36 Cov.: 32 AF XY: 0.00555 AC XY: 3977 AN XY: 717176

African (AFR) AF: 0.00132 AC: 44 AN: 33298

American (AMR) AF: 0.00159 AC: 67 AN: 42134

Ashkenazi Jewish (ASJ) AF: 0.000156 AC: 4 AN: 25706

East Asian (EAS) AF: 0.00 AC: 0 AN: 39172

South Asian (SAS) AF: 0.000878 AC: 73 AN: 83178

European-Finnish (FIN) AF: 0.0000959 AC: 5 AN: 52118

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5758

European-Non Finnish (NFE) AF: 0.00703 AC: 7768 AN: 1104332

Other (OTH) AF: 0.00557 AC: 333 AN: 59818

GnomAD4 genome AF: 0.00307 AC: 468 AN: 152264 Hom.: 3 Cov.: 32 AF XY: 0.00281 AC XY: 209 AN XY: 74448

African (AFR) AF: 0.00113 AC: 47 AN: 41558

American (AMR) AF: 0.00281 AC: 43 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00548 AC: 373 AN: 68016

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00411 Hom.: 8

Bravo AF: 0.00346

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00558 AC: 48

ExAC AF: 0.00196 AC: 237

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	3	Cohen syndrome (3)
-	-	3	not specified (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability (1)
-	-	1	VPS13B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.3	L
PhyloP100		9.2
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MVP		0.73
MPC		0.30
ClinPred		0.038	T
GERP RS		5.7
Varity_R		0.72
gMVP		0.93
Mutation Taster		=73/27	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: rs142476821; hg19: chr8-100874030; COSMIC: COSV62153126;