16-19616768-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000417362.7(VPS35L):ā€‹c.1184T>Cā€‹(p.Met395Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

VPS35L
ENST00000417362.7 missense

Scores

1
8
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3190757).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
VPS35LNM_020314.7 linkuse as main transcriptc.1184T>C p.Met395Thr missense_variant 14/31 ENST00000417362.7 NP_064710.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
VPS35LENST00000417362.7 linkuse as main transcriptc.1184T>C p.Met395Thr missense_variant 14/311 NM_020314.7 ENSP00000395973 P1Q7Z3J2-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152198
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00000795
AC:
2
AN:
251462
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.000123
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461892
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152198
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.00
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:
0.000478
Bravo
AF:
0.0000151

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 27, 2021The c.1451T>C (p.M484T) alteration is located in exon 14 (coding exon 14) of the C16orf62 gene. This alteration results from a T to C substitution at nucleotide position 1451, causing the methionine (M) at amino acid position 484 to be replaced by a threonine (T). 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
Uncertain
0.39
BayesDel_addAF
Benign
0.0036
T
BayesDel_noAF
Uncertain
-0.050
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.076
T;T;.;.;.;T;.
Eigen
Benign
-0.041
Eigen_PC
Benign
0.19
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
.;D;D;D;D;D;D
M_CAP
Benign
0.038
D
MetaRNN
Benign
0.32
T;T;T;T;T;T;T
MetaSVM
Benign
-0.93
T
MutationTaster
Benign
1.0
D;D;D;D;D;D
PROVEAN
Uncertain
-2.7
D;.;.;.;N;N;.
REVEL
Uncertain
0.31
Sift
Uncertain
0.0040
D;.;.;.;D;D;.
Sift4G
Uncertain
0.0060
D;D;D;D;D;D;D
Polyphen
0.0090
B;B;.;.;.;.;.
Vest4
0.77
MutPred
0.54
Loss of stability (P = 0.0267);Loss of stability (P = 0.0267);.;.;.;.;.;
MVP
0.51
MPC
0.28
ClinPred
0.46
T
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
gMVP
0.73

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: rs912416676; hg19: chr16-19628090; API