chr16-89709418-C-T

Variant summary

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

The NM_004913.3(VPS9D1):​c.1406G>A​(p.Arg469Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000672 in 1,516,760 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 0.000026 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

VPS9D1
NM_004913.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.798
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=0.06628153).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
VPS9D1NM_004913.3 linkuse as main transcriptc.1406G>A p.Arg469Gln 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.1406G>A p.Arg469Gln missense_variant 12/151 NM_004913.3 ENSP00000374037 A2Q9Y2B5-1
VPS9D1ENST00000561976.5 linkuse as main transcriptc.1196G>A p.Arg399Gln missense_variant 11/141 ENSP00000454244 P2
VPS9D1ENST00000565023.1 linkuse as main transcriptc.209G>A p.Arg70Gln missense_variant 3/65 ENSP00000455792

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152118
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:
0.000414
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000859
AC:
14
AN:
162900
Hom.:
0
AF XY:
0.000114
AC XY:
10
AN XY:
87862
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000461
Gnomad ASJ exome
AF:
0.000296
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000732
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000125
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000718
AC:
98
AN:
1364524
Hom.:
0
Cov.:
32
AF XY:
0.0000999
AC XY:
67
AN XY:
670428
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000324
Gnomad4 ASJ exome
AF:
0.0000496
Gnomad4 EAS exome
AF:
0.0000257
Gnomad4 SAS exome
AF:
0.000950
Gnomad4 FIN exome
AF:
0.0000250
Gnomad4 NFE exome
AF:
0.0000205
Gnomad4 OTH exome
AF:
0.0000710
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152236
Hom.:
0
Cov.:
31
AF XY:
0.0000403
AC XY:
3
AN XY:
74422
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:
0.000414
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000108
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.000119
AC:
14

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 24, 2023The c.1406G>A (p.R469Q) alteration is located in exon 12 (coding exon 12) of the VPS9D1 gene. This alteration results from a G to A substitution at nucleotide position 1406, causing the arginine (R) at amino acid position 469 to be replaced by a glutamine (Q). 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
0.087
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.033
.;T
Eigen
Benign
-0.52
Eigen_PC
Benign
-0.53
FATHMM_MKL
Benign
0.21
N
LIST_S2
Benign
0.78
T;T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.066
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.5
.;L
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-1.1
N;N
REVEL
Benign
0.033
Sift
Benign
0.16
T;T
Sift4G
Benign
0.11
T;T
Polyphen
0.23
.;B
Vest4
0.32
MutPred
0.44
.;Loss of MoRF binding (P = 0.0458);
MVP
0.25
MPC
0.21
ClinPred
0.092
T
GERP RS
2.1
Varity_R
0.070
gMVP
0.37

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs768244692; hg19: chr16-89775826; API