Genetic Variant VPS9D1:p.Pro554Thr (chr16-89708894-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004913.3(VPS9D1):c.1660C>A(p.Pro554Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,596,518 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 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

VPS9D1
NM_004913.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.104

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08871251).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS9D1	NM_004913.3 link	c.1660C>A	p.Pro554Thr	missense_variant	Exon 13 of 15	ENST00000389386.8	NP_004904.2	Q9Y2B5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VPS9D1	ENST00000389386.8 link	c.1660C>A	p.Pro554Thr	missense_variant	Exon 13 of 15	1	NM_004913.3	ENSP00000374037.3	Q9Y2B5-1
VPS9D1	ENST00000561976.5 link	c.1450C>A	p.Pro484Thr	missense_variant	Exon 12 of 14	1		ENSP00000454244.1	H3BM58
VPS9D1	ENST00000565023.1 link	c.460C>A	p.Pro154Thr	missense_variant	Exon 4 of 6	5		ENSP00000455792.1	H3BQI2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

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:

6.92e-7

AC:

AN:

1444202

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32608

American (AMR)

AF:

0.00

AC:

AN:

39796

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25302

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39520

South Asian (SAS)

AF:

0.00

AC:

AN:

83350

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5460

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107014

Other (OTH)

AF:

0.00

AC:

AN:

59556

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

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41570

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2108

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1660C>A (p.P554T) alteration is located in exon 13 (coding exon 13) of the VPS9D1 gene. This alteration results from a C to A substitution at nucleotide position 1660, causing the proline (P) at amino acid position 554 to be replaced by a threonine (T). 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

0.063

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.030

.;T

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.38

T;T

M_CAP

Benign

0.0088

MetaRNN

Benign

0.089

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

.;L

PhyloP100

-0.10

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.096

Sift

Benign

0.87

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.44

.;B

Vest4

0.21

MutPred

0.38

.;Gain of glycosylation at P554 (P = 0.0181);

MVP

0.10

MPC

0.20

ClinPred

0.13

GERP RS

2.0

Varity_R

0.025

gMVP

0.27

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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16-89708894-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over