Genetic Variant VPS9D1:p.His249Gln (chr16-89711882-A-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_004913.3(VPS9D1):c.747T>A(p.His249Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H249H) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

VPS9D1
NM_004913.3 missense, splice_region

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.72

Publications

2 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:

VPS9D1-AS1 (HGNC:48915): (VPS9D1 antisense RNA 1)

VPS9D1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39463693).

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.747T>A	p.His249Gln	missense splice_region	Exon 8 of 15	NP_004904.2	Q9Y2B5-1
	VPS9D1-AS1	NR_036480.1		n.27A>T		non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VPS9D1	ENST00000389386.8	TSL:1 MANE Select	c.747T>A	p.His249Gln	missense splice_region	Exon 8 of 15	ENSP00000374037.3	Q9Y2B5-1
VPS9D1	ENST00000561976.5	TSL:1	c.537T>A	p.His179Gln	missense splice_region	Exon 7 of 14	ENSP00000454244.1	H3BM58
VPS9D1	ENST00000563798.1	TSL:3	n.*256T>A		splice_region non_coding_transcript_exon	Exon 5 of 6	ENSP00000454889.1	H3BNK1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1398324

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689704

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31598

American (AMR)

AF:

0.00

AC:

AN:

35720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25158

East Asian (EAS)

AF:

0.00

AC:

AN:

35756

South Asian (SAS)

AF:

0.00

AC:

AN:

79244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48478

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5672

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1078738

Other (OTH)

AF:

0.00

AC:

AN:

57960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Benign

8.2

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.35

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.83

M_CAP

Benign

0.024

MetaRNN

Benign

0.39

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

PhyloP100

-1.7

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.15

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.019

Polyphen

1.0

Vest4

0.58

MutPred

0.21

Gain of solvent accessibility (P = 0.0155)

MVP

0.25

MPC

0.48

ClinPred

0.99

GERP RS

-4.3

Varity_R

0.35

gMVP

0.51

Mutation Taster

=56/44

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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