Genetic Variant VPS9D1:p.Gly557Arg (chr16-89708885-C-T) – 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.1669G>A(p.Gly557Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000504 in 1,587,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

VPS9D1
NM_004913.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.779

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:

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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=0.05695808).

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.1669G>A	p.Gly557Arg	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.1669G>A	p.Gly557Arg	missense	Exon 13 of 15	ENSP00000374037.3	Q9Y2B5-1
VPS9D1	ENST00000561976.5	TSL:1	c.1459G>A	p.Gly487Arg	missense	Exon 12 of 14	ENSP00000454244.1	H3BM58
VPS9D1	ENST00000906741.1		c.1714G>A	p.Gly572Arg	missense	Exon 13 of 15	ENSP00000576800.1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000855

AC:

AN:

210432

AF XY:

0.0000772

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000762

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000630

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000143

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000481

AC:

AN:

1435468

Hom.:

Cov.:

AF XY:

0.0000574

AC XY:

AN XY:

713776

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31954

American (AMR)

AF:

0.000110

AC:

AN:

36416

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24836

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39476

South Asian (SAS)

AF:

0.0000122

AC:

AN:

81770

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51464

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5472

European-Non Finnish (NFE)

AF:

0.0000543

AC:

AN:

1104900

Other (OTH)

AF:

0.0000507

AC:

AN:

59180

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

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:

0.0000723

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41452

American (AMR)

AF:

0.000262

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000149

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.0000585

AC:

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

0.10

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.018

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.49

M_CAP

Benign

0.0099

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.26

PhyloP100

0.78

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.98

REVEL

Benign

0.020

Sift

Benign

0.17

Sift4G

Benign

0.25

Polyphen

0.015

Vest4

0.061

MutPred

0.42

Gain of solvent accessibility (P = 0.0037)

MVP

0.12

MPC

0.22

ClinPred

0.018

GERP RS

-1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.058

gMVP

0.23

Mutation Taster

=98/2

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over