16-19652055-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_020314.7(VPS35L):ā€‹c.2186G>Cā€‹(p.Gly729Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

VPS35L
NM_020314.7 missense

Scores

6
5
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.71
Variant links:
Genes affected
VPS35L (HGNC:24641): (VPS35 endosomal protein sorting factor like) Involved in Golgi to plasma membrane transport and endocytic recycling. Located in endosome. Implicated in Ritscher-Schinzel syndrome. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
VPS35LNM_020314.7 linkuse as main transcriptc.2186G>C p.Gly729Ala missense_variant 26/31 ENST00000417362.7 NP_064710.5 Q7Z3J2-1E7EWW0

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
VPS35LENST00000417362.7 linkuse as main transcriptc.2186G>C p.Gly729Ala missense_variant 26/311 NM_020314.7 ENSP00000395973.3 Q7Z3J2-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1459578
Hom.:
0
Cov.:
31
AF XY:
0.00000276
AC XY:
2
AN XY:
725832
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxNov 20, 2023Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.34
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.16
T;T;.;.;.;T
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
.;D;D;D;D;D
M_CAP
Benign
0.014
T
MetaRNN
Pathogenic
0.83
D;D;D;D;D;D
MetaSVM
Benign
-0.40
T
PROVEAN
Uncertain
-4.1
D;.;D;.;D;D
REVEL
Uncertain
0.51
Sift
Benign
0.13
T;.;T;.;T;T
Sift4G
Benign
0.067
T;T;T;T;T;T
Polyphen
1.0
.;.;D;.;.;.
Vest4
0.93
MutPred
0.43
.;.;.;Loss of glycosylation at S728 (P = 0.0568);.;.;
MVP
0.72
MPC
0.43
ClinPred
0.95
D
GERP RS
6.0
gMVP
0.75

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-19663377; API