11-119067888-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_021729.6(VPS11):ā€‹c.65T>Cā€‹(p.Leu22Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000503 in 1,590,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000028 ( 0 hom. )

Consequence

VPS11
NM_021729.6 missense

Scores

9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.184
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.028403878).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VPS11NM_021729.6 linkc.65T>C p.Leu22Pro missense_variant Exon 1 of 16 ENST00000621676.5 NP_068375.3 Q9H270A0A087WXL6B7Z879

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VPS11ENST00000621676.5 linkc.65T>C p.Leu22Pro missense_variant Exon 1 of 16 1 NM_021729.6 ENSP00000481126.1 A0A087WXL6
VPS11ENST00000614944 linkc.-181T>C 5_prime_UTR_variant Exon 1 of 16 2 ENSP00000481807.1 B7Z879
VPS11ENST00000622309.4 linkn.66T>C non_coding_transcript_exon_variant Exon 1 of 13 5

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152220
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00000474
AC:
1
AN:
210976
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
114412
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000108
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000278
AC:
4
AN:
1437848
Hom.:
0
Cov.:
31
AF XY:
0.00000421
AC XY:
3
AN XY:
713254
show subpopulations
Gnomad4 AFR exome
AF:
0.0000303
Gnomad4 AMR exome
AF:
0.0000494
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.09e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152338
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74496
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Bravo
AF:
0.0000264
ExAC
AF:
0.00000829
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Aug 04, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.65T>C (p.L22P) alteration is located in exon 1 (coding exon 1) of the VPS11 gene. This alteration results from a T to C substitution at nucleotide position 65, causing the leucine (L) at amino acid position 22 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.051
BayesDel_addAF
Benign
-0.097
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
18
DANN
Benign
0.79
FATHMM_MKL
Benign
0.12
N
M_CAP
Benign
0.041
D
MetaRNN
Benign
0.028
T
PrimateAI
Benign
0.38
T
Sift4G
Benign
0.30
T
Vest4
0.083
MVP
0.54
GERP RS
1.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
gMVP
0.47

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.

Other links and lift over

dbSNP: rs538262767; hg19: chr11-118938599; API