chr11-119081463-A-C

Position:

• chr11-119081463-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000621676.5(VPS11):​c.2666A>C​(p.Lys889Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K889R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: VPS11 ENST00000621676.5 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32483888).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS11	NM_021729.6	c.2666A>C	p.Lys889Thr	missense_variant	16/16	ENST00000621676.5	NP_068375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS11	ENST00000621676.5	c.2666A>C	p.Lys889Thr	missense_variant	16/16	1	NM_021729.6	ENSP00000481126	P1
VPS11	ENST00000614944.4	c.2636A>C	p.Lys879Thr	missense_variant	16/16	2		ENSP00000481807
VPS11	ENST00000524454.1	n.124A>C		non_coding_transcript_exon_variant	2/2	2
VPS11	ENST00000622309.4	n.2851A>C		non_coding_transcript_exon_variant	13/13	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 55

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	23
DANN	Benign	0.87
DEOGEN2	Benign	0.066	.;T;T
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.32	T;T;T
PrimateAI	Uncertain	0.70	T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.14	.;B;.
Vest4		0.30
MVP		0.65
GERP RS		5.7
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs15818; hg19: chr11-118952173;