Genetic Variant NM_004913.3:c.1628C>T (chr16-89708926-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004913.3(VPS9D1):c.1628C>T(p.Ala543Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000811 in 1,603,946 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

VPS9D1
NM_004913.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.31

Publications

3 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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS9D1	NM_004913.3 link	c.1628C>T	p.Ala543Val	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.1628C>T	p.Ala543Val	missense_variant	Exon 13 of 15	1	NM_004913.3	ENSP00000374037.3	Q9Y2B5-1
VPS9D1	ENST00000561976.5 link	c.1418C>T	p.Ala473Val	missense_variant	Exon 12 of 14	1		ENSP00000454244.1	H3BM58
VPS9D1	ENST00000565023.1 link	c.428C>T	p.Ala143Val	missense_variant	Exon 4 of 6	5		ENSP00000455792.1	H3BQI2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152154

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

GnomAD2 exomes

AF:

0.00000872

AC:

AN:

229352

AF XY:

0.0000159

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000117

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000827

AC:

AN:

1451792

Hom.:

Cov.:

AF XY:

0.00000970

AC XY:

AN XY:

721838

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33226

American (AMR)

AF:

0.00

AC:

AN:

43110

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25764

East Asian (EAS)

AF:

0.0000760

AC:

AN:

39448

South Asian (SAS)

AF:

0.00

AC:

AN:

84660

European-Finnish (FIN)

AF:

0.0000194

AC:

AN:

51510

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5348

European-Non Finnish (NFE)

AF:

0.00000631

AC:

AN:

1108840

Other (OTH)

AF:

0.00

AC:

AN:

59886

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:

152154

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2092

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

Alfa

AF:

0.0000712

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

Oct 01, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1628C>T (p.A543V) alteration is located in exon 13 (coding exon 13) of the VPS9D1 gene. This alteration results from a C to T substitution at nucleotide position 1628, causing the alanine (A) at amino acid position 543 to be replaced by a valine (V). 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

Uncertain

0.41

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.035

.;T

Eigen

Benign

0.14

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.025

MetaRNN

Uncertain

0.70

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

.;M

PhyloP100

7.3

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.73

N;N

REVEL

Benign

0.23

Sift

Benign

0.30

T;T

Sift4G

Benign

0.18

T;T

Polyphen

0.96

.;D

Vest4

0.70

MutPred

0.50

.;Loss of catalytic residue at A543 (P = 0.0226);

MVP

0.36

MPC

0.29

ClinPred

0.73

GERP RS

4.9

Varity_R

0.10

gMVP

0.54

Mutation Taster

=71/29

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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NM_004913.3:c.1628C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over