11-119081463-A-C

Variant names:

• chr11-119081463-A-C
• rs15818
• NM_021729.6:c.2666A>C
• VPS11 p.Lys889Thr

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021729.6(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 NM_021729.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.41
• Publications: 46 publications found

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: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS11	NM_021729.6	MANE Select	c.2666A>C	p.Lys889Thr	missense	Exon 16 of 16	NP_068375.3
	VPS11	NM_001378218.1		c.2678A>C	p.Lys893Thr	missense	Exon 16 of 16	NP_001365147.1
	VPS11	NM_001378219.1		c.2678A>C	p.Lys893Thr	missense	Exon 16 of 16	NP_001365148.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS11	ENST00000621676.5	TSL:1 MANE Select	c.2666A>C	p.Lys889Thr	missense	Exon 16 of 16	ENSP00000481126.1	A0A087WXL6
	VPS11	ENST00000952525.1		c.2756A>C	p.Lys919Thr	missense	Exon 16 of 16	ENSP00000622584.1
	VPS11	ENST00000863302.1		c.2678A>C	p.Lys893Thr	missense	Exon 16 of 16	ENSP00000533361.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 55

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 45951

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.32	T
PhyloP100		5.4
PrimateAI	Uncertain	0.70	T
Sift4G	Benign	0.11	T
gMVP		0.37
Mutation Taster		=76/24	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs15818;

hg19: chr11-118952173;