Genetic Variant NM_004913.3:c.83C>A (chr16-89720779-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.83C>A(p.Thr28Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000767 in 1,303,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T28S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

VPS9D1
NM_004913.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.43

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:

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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=0.24300364).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS9D1	NM_004913.3 link	c.83C>A	p.Thr28Asn	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.83C>A	p.Thr28Asn	missense_variant	Exon 1 of 15	1	NM_004913.3	ENSP00000374037.3		Q9Y2B5-1
VPS9D1	ENST00000563798.1 link	n.83C>A		non_coding_transcript_exon_variant	Exon 1 of 6	3		ENSP00000454889.1		H3BNK1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.67e-7

AC:

AN:

1303768

Hom.:

Cov.:

AF XY:

0.00000156

AC XY:

AN XY:

642978

show subpopulations

African (AFR)

AF:

0.0000380

AC:

AN:

26342

American (AMR)

AF:

0.00

AC:

AN:

25608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22410

East Asian (EAS)

AF:

0.00

AC:

AN:

26956

South Asian (SAS)

AF:

0.00

AC:

AN:

69924

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4802

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1032624

Other (OTH)

AF:

0.00

AC:

AN:

53068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.022

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.72

M_CAP

Pathogenic

0.56

MetaRNN

Benign

0.24

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

2.4

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.1

REVEL

Benign

0.026

Sift

Uncertain

0.018

Sift4G

Benign

0.12

Polyphen

0.38

Vest4

0.14

MutPred

0.18

Loss of phosphorylation at T28 (P = 0.036);

MVP

0.061

MPC

0.68

ClinPred

0.62

GERP RS

3.0

PromoterAI

0.046

Neutral

(source)

Varity_R

0.20

gMVP

0.12

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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NM_004913.3:c.83C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over