Genetic Variant VPS9D1:p.Pro548Leu (chr16-89708911-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004913.3(VPS9D1):c.1643C>T(p.Pro548Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,600,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

VPS9D1
NM_004913.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.247

Publications

0 publications found

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]

VPS9D1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.031389266).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004913.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS9D1	NM_004913.3	MANE Select	c.1643C>T	p.Pro548Leu	missense	Exon 13 of 15	NP_004904.2	Q9Y2B5-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VPS9D1	ENST00000389386.8	TSL:1 MANE Select	c.1643C>T	p.Pro548Leu	missense	Exon 13 of 15	ENSP00000374037.3	Q9Y2B5-1
VPS9D1	ENST00000561976.5	TSL:1	c.1433C>T	p.Pro478Leu	missense	Exon 12 of 14	ENSP00000454244.1	H3BM58
VPS9D1	ENST00000906741.1		c.1688C>T	p.Pro563Leu	missense	Exon 13 of 15	ENSP00000576800.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1448504

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720266

show subpopulations

African (AFR)

AF:

0.0000608

AC:

AN:

32908

American (AMR)

AF:

0.00

AC:

AN:

41790

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25550

East Asian (EAS)

AF:

0.00

AC:

AN:

39456

South Asian (SAS)

AF:

0.00

AC:

AN:

84066

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5404

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108014

Other (OTH)

AF:

0.00

AC:

AN:

59762

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

7.5

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.0096

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.089

LIST_S2

Benign

0.74

M_CAP

Benign

0.0074

MetaRNN

Benign

0.031

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-1.4

PhyloP100

0.25

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.20

REVEL

Benign

0.026

Sift

Benign

0.31

Sift4G

Benign

0.30

Polyphen

0.0010

Vest4

0.085

MutPred

0.46

Loss of disorder (P = 0.0219)

MVP

0.12

MPC

0.18

ClinPred

0.12

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.031

gMVP

0.20

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over