Genetic Variant VPS9D1:p.Asn30Ser (chr16-89720773-T-C) – 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.89A>G(p.Asn30Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

VPS9D1
NM_004913.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.33

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:

ZNF276 (HGNC:23330): (zinc finger protein 276) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in kinetochore. [provided by Alliance of Genome Resources, Apr 2022]

ZNF276 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=0.2340233).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS9D1	NM_004913.3 link	c.89A>G	p.Asn30Ser	missense_variant	Exon 1 of 15	ENST00000389386.8	NP_004904.2	Q9Y2B5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS9D1	ENST00000389386.8 link	c.89A>G	p.Asn30Ser	missense_variant	Exon 1 of 15	1	NM_004913.3	ENSP00000374037.3		Q9Y2B5-1
VPS9D1	ENST00000563798.1 link	n.89A>G		non_coding_transcript_exon_variant	Exon 1 of 6	3		ENSP00000454889.1		H3BNK1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151902

Hom.:

Cov.:

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:

0.000195

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1299918

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

641004

African (AFR)

AF:

0.00

AC:

AN:

26290

American (AMR)

AF:

0.00

AC:

AN:

25392

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22336

East Asian (EAS)

AF:

0.00

AC:

AN:

26878

South Asian (SAS)

AF:

0.00

AC:

AN:

69406

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41438

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4670

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1030644

Other (OTH)

AF:

0.00

AC:

AN:

52864

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151902

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74204

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41396

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000195

AC:

AN:

5140

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10558

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67934

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 26, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.89A>G (p.N30S) alteration is located in exon 1 (coding exon 1) of the VPS9D1 gene. This alteration results from a A to G substitution at nucleotide position 89, causing the asparagine (N) at amino acid position 30 to be replaced by a serine (S). 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

0.11

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.020

Eigen

Benign

0.043

Eigen_PC

Benign

0.040

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.75

M_CAP

Pathogenic

0.58

MetaRNN

Benign

0.23

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

PhyloP100

1.3

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.99

REVEL

Benign

0.069

Sift

Uncertain

0.017

Sift4G

Uncertain

0.019

Polyphen

0.88

Vest4

0.14

MutPred

0.16

Gain of phosphorylation at N30 (P = 0.0317);

MVP

0.62

MPC

0.28

ClinPred

0.65

GERP RS

2.9

PromoterAI

-0.0060

Neutral

(source)

Varity_R

0.17

gMVP

0.10

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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16-89720773-T-C

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