rs34757931

Positions:

chr11-119081189-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_ModeratePM2PP5_Very_Strong

The NM_021729.6(VPS11):c.2536T>G(p.Cys846Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

VPS11
NM_021729.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.81

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PS1

Transcript NM_021729.6 (VPS11) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-119081189-T-G is Pathogenic according to our data. Variant chr11-119081189-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 218366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS11	NM_021729.6 linkuse as main transcript	c.2536T>G	p.Cys846Gly	missense_variant	15/16	ENST00000621676.5	NP_068375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
VPS11	ENST00000621676.5 linkuse as main transcript	c.2536T>G	p.Cys846Gly	missense_variant	15/16	1	NM_021729.6	ENSP00000481126	P1
VPS11	ENST00000614944.4 linkuse as main transcript	c.2506T>G	p.Cys836Gly	missense_variant	15/16	2		ENSP00000481807
VPS11	ENST00000622309.4 linkuse as main transcript	n.2721T>G		non_coding_transcript_exon_variant	12/13	5
VPS11	ENST00000524454.1 linkuse as main transcript	n.120-270T>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000116

AC:

AN:

249276

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

135230

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000527

AC:

AN:

1461712

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00237

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000315

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000909

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypomyelinating leukodystrophy 12

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 16, 2020	The homozygous p.Cys846Gly variant in VPS11 was identified by our study in 1 individual with hypomyelinating leukodystrophy 12. The variant has been reported in 13 Ashkenazi Jewish individuals with hypomyelinating leukodystrophy 12 (PMID: 26307567, 27120463), segregated with disease in 6 affected relatives from 4 families (PMID: 26307567, 27120463). This variant has been identified in 0.26% (27/10352) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs34757931). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 218366) as pathogenic by Baylor Genetics and OMIM. Of the 14 affected individuals, all of them were homozygotes, which increases the likelihood that the p.Cys846Gly variant is pathogenic (PMID: 26307567, 27120463). In vitro functional studies provide some evidence that the p.Cys846Gly variant may impact protein function (PMID: 26307567, 27120463, 32316234). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PP1_strong, PM3, PP3, PS3_moderate (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 04, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been reported at the homozygous state in multiple patients from Ashkenazi Jewish descent [PMID 26307567] -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 06, 2024	Variant summary: VPS11 c.2533T>G/p.Cys845Gly (also known as c.2536T>G/p.Cys846Gly in Refseq) results in a non-conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 249276 control chromosomes. c.2533T>G has been reported in the literature in multiple individuals affected with Hypomyelinating Leukodystrophy 12. These data indicate that the variant is very likely to be associated with disease. ClinVar contains an entry for this variant (Variation ID: 218366). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2015	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2021	Published functional studies demonstrate a damaging effect: decreased protein stability compared to wildtype (Zhang et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31980526, 31092635, 29431110, 27473128, 26307567, 27120463) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 846 of the VPS11 protein (p.Cys846Gly). This variant is present in population databases (rs34757931, gnomAD 0.2%). This missense change has been observed in individuals with clinical features of VPS11-related conditions (PMID: 26307567, 27120463). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218366). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VPS11 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects VPS11 function (PMID: 26307567, 27120463). For these reasons, this variant has been classified as Pathogenic. -

Leukoencephalopathy

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing;research

Baylor Genetics

Dec 17, 2015

We identified it, homozygous, in 5 affected individuals in 3 Ashkenazi Jewish families. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Benign

0.84

DEOGEN2

Benign

0.40

.;T;D

FATHMM_MKL

Pathogenic

1.0

M_CAP

Benign

0.084

MetaRNN

Uncertain

0.50

T;T;T

PrimateAI

Pathogenic

0.86

Sift4G

Uncertain

0.0090

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.97

MVP

0.53

GERP RS

5.9

gMVP

0.85

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over