11-119081463-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.41

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 11-119081463-A-G is Benign according to our data. Variant chr11-119081463-A-G is described in ClinVar as [Benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS11	NM_021729.6	c.2666A>G	p.Lys889Arg	missense_variant	16/16	ENST00000621676.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS11	ENST00000621676.5	c.2666A>G	p.Lys889Arg	missense_variant	16/16	1	NM_021729.6	P1
VPS11	ENST00000614944.4	c.2636A>G	p.Lys879Arg	missense_variant	16/16	2
VPS11	ENST00000524454.1	n.124A>G		non_coding_transcript_exon_variant	2/2	2
VPS11	ENST00000622309.4	n.2851A>G		non_coding_transcript_exon_variant	13/13	5

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60584 AN: 151878 Hom.: 12503 Cov.: 31

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

GnomAD3 exomes AF: 0.357 AC: 88984 AN: 249132 Hom.: 16982 AF XY: 0.361 AC XY: 48847 AN XY: 135166

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 SAS exome AF: 0.360

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.: 55 AF XY: 0.390 AC XY: 283584 AN XY: 727074

Gnomad4 AFR exome AF: 0.472

Gnomad4 AMR exome AF: 0.285

Gnomad4 ASJ exome AF: 0.415

Gnomad4 EAS exome AF: 0.140

Gnomad4 SAS exome AF: 0.360

Gnomad4 FIN exome AF: 0.291

Gnomad4 NFE exome AF: 0.407

Gnomad4 OTH exome AF: 0.389

GnomAD4 genome AF: 0.399 AC: 60615 AN: 151996 Hom.: 12512 Cov.: 31 AF XY: 0.391 AC XY: 29020 AN XY: 74282

Gnomad4 AFR AF: 0.471

Gnomad4 AMR AF: 0.347

Gnomad4 ASJ AF: 0.406

Gnomad4 EAS AF: 0.172

Gnomad4 SAS AF: 0.351

Gnomad4 FIN AF: 0.285

Gnomad4 NFE AF: 0.403

Gnomad4 OTH AF: 0.416

Alfa AF: 0.397 Hom.: 22532

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Benign	21
Dann	Benign	0.87
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.0033	T;T;T
PrimateAI	Uncertain	0.63	T
Sift4G	Benign	0.69	T;T;T
Polyphen		0.0010	.;B;.
Vest4		0.074
GERP RS		5.7
gMVP		0.16

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

LitVar

Other links and lift over

dbSNP: rs15818; hg19: chr11-118952173; COSMIC: COSV53827913; COSMIC: COSV53827913;