NM_021729.6:c.2666A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBA1

The NM_021729.6(VPS11):c.2666A>G(p.Lys889Arg) variant causes a missense change. The variant allele was found at a frequency of 0.391 in 1,613,586 control chromosomes in the GnomAD database, including 126,288 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 12512 hom., cov: 31)

Exomes 𝑓: 0.39 ( 113776 hom. )

Consequence

VPS11
NM_021729.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 5.41

Publications

46 publications found

Variant links:

Genes affected

VPS11 (HGNC:14583): (VPS11 core subunit of CORVET and HOPS complexes) Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene encodes the human homolog of yeast class C Vps11 protein. The mammalian class C Vps proteins are predominantly associated with late endosomes/lysosomes, and like their yeast counterparts, may mediate vesicle trafficking steps in the endosome/lysosome pathway. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

VPS11 Gene-Disease associations (from GenCC):

VPS11-related neurological disorder
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hypomyelinating leukodystrophy 12
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

VPS11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 11-119081463-A-G is Benign according to our data. Variant chr11-119081463-A-G is described in ClinVar as Benign. ClinVar VariationId is 1168497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021729.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
VPS11	NM_021729.6	MANE Select	c.2666A>G	p.Lys889Arg	missense	Exon 16 of 16	NP_068375.3
VPS11	NM_001378218.1		c.2678A>G	p.Lys893Arg	missense	Exon 16 of 16	NP_001365147.1
VPS11	NM_001378219.1		c.2678A>G	p.Lys893Arg	missense	Exon 16 of 16	NP_001365148.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VPS11	ENST00000621676.5	TSL:1 MANE Select	c.2666A>G	p.Lys889Arg	missense	Exon 16 of 16	ENSP00000481126.1	A0A087WXL6
VPS11	ENST00000952525.1		c.2756A>G	p.Lys919Arg	missense	Exon 16 of 16	ENSP00000622584.1
VPS11	ENST00000863302.1		c.2678A>G	p.Lys893Arg	missense	Exon 16 of 16	ENSP00000533361.1

Frequencies

GnomAD3 genomes

AF:

0.399

AC:

60584

AN:

151878

Hom.:

12503

Cov.:

show subpopulations

Gnomad AFR

AF:

0.471

Gnomad AMI

AF:

0.423

Gnomad AMR

AF:

0.347

Gnomad ASJ

AF:

0.406

Gnomad EAS

AF:

0.172

Gnomad SAS

AF:

0.351

Gnomad FIN

AF:

0.285

Gnomad MID

AF:

0.434

Gnomad NFE

AF:

0.404

Gnomad OTH

AF:

0.416

GnomAD2 exomes

AF:

0.357

AC:

88984

AN:

249132

AF XY:

0.361

show subpopulations

Gnomad AFR exome

AF:

0.472

Gnomad AMR exome

AF:

0.276

Gnomad ASJ exome

AF:

0.415

Gnomad EAS exome

AF:

0.175

Gnomad FIN exome

AF:

0.288

Gnomad NFE exome

AF:

0.402

Gnomad OTH exome

AF:

0.376

GnomAD4 exome

AF:

0.390

AC:

570306

AN:

1461590

Hom.:

113776

Cov.:

AF XY:

0.390

AC XY:

283584

AN XY:

727074

show subpopulations

African (AFR)

AF:

0.472

AC:

15801

AN:

33476

American (AMR)

AF:

0.285

AC:

12741

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.415

AC:

10850

AN:

26134

East Asian (EAS)

AF:

0.140

AC:

5572

AN:

39698

South Asian (SAS)

AF:

0.360

AC:

31067

AN:

86258

European-Finnish (FIN)

AF:

0.291

AC:

15545

AN:

53390

Middle Eastern (MID)

AF:

0.399

AC:

2303

AN:

5768

European-Non Finnish (NFE)

AF:

0.407

AC:

452935

AN:

1111774

Other (OTH)

AF:

0.389

AC:

23492

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

20648

41297

61945

82594

103242

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13876

27752

41628

55504

69380

<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:

0.399

AC:

60615

AN:

151996

Hom.:

12512

Cov.:

AF XY:

0.391

AC XY:

29020

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.471

AC:

19520

AN:

41452

American (AMR)

AF:

0.347

AC:

5300

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.406

AC:

1406

AN:

3466

East Asian (EAS)

AF:

0.172

AC:

886

AN:

5150

South Asian (SAS)

AF:

0.351

AC:

1691

AN:

4816

European-Finnish (FIN)

AF:

0.285

AC:

3010

AN:

10576

Middle Eastern (MID)

AF:

0.429

AC:

126

AN:

294

European-Non Finnish (NFE)

AF:

0.403

AC:

27413

AN:

67940

Other (OTH)

AF:

0.416

AC:

877

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1861

3721

5582

7442

9303

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

574

1148

1722

2296

2870

<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:

0.398

Hom.:

45951

Bravo

AF:

0.403

TwinsUK

AF:

0.400

AC:

1482

ALSPAC

AF:

0.390

AC:

1504

ESP6500AA

AF:

0.465

AC:

1865

ESP6500EA

AF:

0.411

AC:

3431

ExAC

AF:

0.364

AC:

43955

Asia WGS

AF:

0.278

AC:

965

AN:

3478

EpiCase

AF:

0.404

EpiControl

AF:

0.403

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.0067

FATHMM_MKL

Uncertain

0.95

MetaRNN

Benign

0.0033

PhyloP100

5.4

PrimateAI

Uncertain

0.63

Sift4G

Benign

0.69

Polyphen

0.0010

Vest4

0.074

GERP RS

5.7

gMVP

0.16

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.78

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.78

Position offset: 1

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