chr16-89709292-G-T

Variant summary

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

The NM_004913.3(VPS9D1):​c.1532C>A​(p.Ala511Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000087 in 1,609,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

VPS9D1
NM_004913.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.61
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 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=0.34641337).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
VPS9D1NM_004913.3 linkuse as main transcriptc.1532C>A p.Ala511Glu missense_variant 12/15 ENST00000389386.8 NP_004904.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
VPS9D1ENST00000389386.8 linkuse as main transcriptc.1532C>A p.Ala511Glu missense_variant 12/151 NM_004913.3 ENSP00000374037 A2Q9Y2B5-1
VPS9D1ENST00000561976.5 linkuse as main transcriptc.1322C>A p.Ala441Glu missense_variant 11/141 ENSP00000454244 P2
VPS9D1ENST00000565023.1 linkuse as main transcriptc.335C>A p.Ala112Glu missense_variant 3/65 ENSP00000455792

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152150
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000831
AC:
2
AN:
240782
Hom.:
0
AF XY:
0.0000152
AC XY:
2
AN XY:
131880
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:
0.0000186
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000755
AC:
11
AN:
1457362
Hom.:
0
Cov.:
32
AF XY:
0.00000828
AC XY:
6
AN XY:
725060
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000990
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152150
Hom.:
0
Cov.:
31
AF XY:
0.0000404
AC XY:
3
AN XY:
74314
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.00000828
AC:
1

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 GeneticsMar 20, 2023The c.1532C>A (p.A511E) alteration is located in exon 12 (coding exon 12) of the VPS9D1 gene. This alteration results from a C to A substitution at nucleotide position 1532, causing the alanine (A) at amino acid position 511 to be replaced by a glutamic acid (E). 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
0.18
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
18
DANN
Benign
0.95
DEOGEN2
Benign
0.033
.;T
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.38
FATHMM_MKL
Benign
0.47
N
LIST_S2
Benign
0.85
D;D
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.35
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.1
.;M
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-1.4
N;N
REVEL
Benign
0.13
Sift
Benign
0.25
T;T
Sift4G
Uncertain
0.025
D;D
Polyphen
0.85
.;P
Vest4
0.45
MutPred
0.49
.;Gain of solvent accessibility (P = 0.0411);
MVP
0.44
MPC
0.24
ClinPred
0.32
T
GERP RS
4.1
Varity_R
0.16
gMVP
0.46

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: rs201610914; hg19: chr16-89775700; API