Genetic Variant NM_017890.5:c.10140G>T (chr8-99853454-G-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_017890.5(VPS13B):c.10140G>T(p.Ala3380Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 1,614,024 control chromosomes in the GnomAD database, including 430 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. A3380A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.017 ( 23 hom., cov: 32)

Exomes 𝑓: 0.022 ( 407 hom. )

Consequence

VPS13B
NM_017890.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.231

Publications

5 publications found

Variant links:

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

VPS13B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 8-99853454-G-T is Benign according to our data. Variant chr8-99853454-G-T is described in ClinVar as Benign. ClinVar VariationId is 459245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.231 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0173 (2634/152290) while in subpopulation NFE AF = 0.0258 (1756/68018). AF 95% confidence interval is 0.0248. There are 23 homozygotes in GnomAd4. There are 1225 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 23 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	NM_017890.5	MANE Plus Clinical	c.10140G>T	p.Ala3380Ala	synonymous	Exon 56 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.10065G>T	p.Ala3355Ala	synonymous	Exon 56 of 62	NP_689777.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
VPS13B	ENST00000358544.7	TSL:1 MANE Plus Clinical	c.10140G>T	p.Ala3380Ala	synonymous	Exon 56 of 62	ENSP00000351346.2
VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.10065G>T	p.Ala3355Ala	synonymous	Exon 56 of 62	ENSP00000349685.2
VPS13B	ENST00000682153.1		n.10140G>T		non_coding_transcript_exon	Exon 56 of 62	ENSP00000507923.1

Frequencies

GnomAD3 genomes

AF:

0.0173

AC:

2635

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00555

Gnomad AMI

AF:

0.0658

Gnomad AMR

AF:

0.0194

Gnomad ASJ

AF:

0.0248

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00725

Gnomad FIN

AF:

0.00970

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0258

Gnomad OTH

AF:

0.0277

GnomAD2 exomes

AF:

0.0174

AC:

4356

AN:

250630

AF XY:

0.0181

show subpopulations

Gnomad AFR exome

AF:

0.00492

Gnomad AMR exome

AF:

0.0148

Gnomad ASJ exome

AF:

0.0222

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00989

Gnomad NFE exome

AF:

0.0260

Gnomad OTH exome

AF:

0.0282

GnomAD4 exome

AF:

0.0224

AC:

32788

AN:

1461734

Hom.:

407

Cov.:

AF XY:

0.0221

AC XY:

16041

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.00427

AC:

143

AN:

33480

American (AMR)

AF:

0.0148

AC:

662

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0235

AC:

615

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00698

AC:

602

AN:

86220

European-Finnish (FIN)

AF:

0.0119

AC:

635

AN:

53418

Middle Eastern (MID)

AF:

0.0295

AC:

170

AN:

5768

European-Non Finnish (NFE)

AF:

0.0258

AC:

28650

AN:

1111902

Other (OTH)

AF:

0.0217

AC:

1311

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

1646

3293

4939

6586

8232

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1056

2112

3168

4224

5280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0173

AC:

2634

AN:

152290

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

1225

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00553

AC:

230

AN:

41562

American (AMR)

AF:

0.0194

AC:

296

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0248

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00726

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00970

AC:

103

AN:

10614

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0258

AC:

1756

AN:

68018

Other (OTH)

AF:

0.0274

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

140

281

421

562

702

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0220

Hom.:

Bravo

AF:

0.0176

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0298

EpiControl

AF:

0.0278

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cohen syndrome (5)

not provided (3)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.037

(source)

DANN

Benign

0.28

PhyloP100

-0.23

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over