chr16-89710808-G-A

Variant summary

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

The NM_004913.3(VPS9D1):​c.1036C>T​(p.Pro346Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,390,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

VPS9D1
NM_004913.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.00100
Variant links:
Genes affected
VPS9D1 (HGNC:13526): (VPS9 domain containing 1) Enables identical protein binding activity. Predicted to be involved in ATP synthesis coupled proton transport. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

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=0.06558448).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
VPS9D1NM_004913.3 linkuse as main transcriptc.1036C>T p.Pro346Ser missense_variant 10/15 ENST00000389386.8 NP_004904.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
VPS9D1ENST00000389386.8 linkuse as main transcriptc.1036C>T p.Pro346Ser missense_variant 10/151 NM_004913.3 ENSP00000374037 A2Q9Y2B5-1
VPS9D1ENST00000561976.5 linkuse as main transcriptc.826C>T p.Pro276Ser missense_variant 9/141 ENSP00000454244 P2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000137
AC:
2
AN:
145476
Hom.:
0
AF XY:
0.0000127
AC XY:
1
AN XY:
78648
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000186
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:
0.00000144
AC:
2
AN:
1390436
Hom.:
0
Cov.:
32
AF XY:
0.00000146
AC XY:
1
AN XY:
684264
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000562
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.0000209
AC:
2

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 GeneticsJan 02, 2024The c.1036C>T (p.P346S) alteration is located in exon 10 (coding exon 10) of the VPS9D1 gene. This alteration results from a C to T substitution at nucleotide position 1036, causing the proline (P) at amino acid position 346 to be replaced by a serine (S). 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
0.082
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
8.6
DANN
Benign
0.76
DEOGEN2
Benign
0.016
.;T
Eigen
Benign
-0.83
Eigen_PC
Benign
-0.84
FATHMM_MKL
Benign
0.19
N
LIST_S2
Benign
0.46
T;T
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.066
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.7
.;L
MutationTaster
Benign
1.0
N;N
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-0.18
N;N
REVEL
Benign
0.011
Sift
Benign
0.14
T;T
Sift4G
Benign
0.86
T;T
Polyphen
0.035
.;B
Vest4
0.064
MutPred
0.19
.;Gain of phosphorylation at P346 (P = 0.0024);
MVP
0.13
MPC
0.18
ClinPred
0.027
T
GERP RS
1.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.026
gMVP
0.22

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: rs762484469; hg19: chr16-89777216; API