Genetic Variant VPS9D1:p.Leu185Leu (chr16-89712511-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004913.3(VPS9D1):c.555A>G(p.Leu185Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,612,864 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 86 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 46 hom. )

Consequence

VPS9D1
NM_004913.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.344

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 16-89712511-T-C is Benign according to our data. Variant chr16-89712511-T-C is described in ClinVar as Benign. ClinVar VariationId is 768806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.344 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0552 is higher than 0.05.

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.555A>G	p.Leu185Leu	synonymous	Exon 6 of 15	NP_004904.2	Q9Y2B5-1
	VPS9D1-AS1	NR_036480.1		n.368-178T>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VPS9D1	ENST00000389386.8	TSL:1 MANE Select	c.555A>G	p.Leu185Leu	synonymous	Exon 6 of 15	ENSP00000374037.3	Q9Y2B5-1
VPS9D1	ENST00000561976.5	TSL:1	c.345A>G	p.Leu115Leu	synonymous	Exon 5 of 14	ENSP00000454244.1	H3BM58
VPS9D1	ENST00000563798.1	TSL:3	n.*64A>G		non_coding_transcript_exon	Exon 3 of 6	ENSP00000454889.1	H3BNK1

Frequencies

GnomAD3 genomes

AF:

0.0165

AC:

2508

AN:

151886

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0570

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00805

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00910

GnomAD2 exomes

AF:

0.00398

AC:

987

AN:

247910

AF XY:

0.00292

show subpopulations

Gnomad AFR exome

AF:

0.0560

Gnomad AMR exome

AF:

0.00313

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000711

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.00156

AC:

2284

AN:

1460860

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

952

AN XY:

726748

show subpopulations

African (AFR)

AF:

0.0557

AC:

1865

AN:

33472

American (AMR)

AF:

0.00340

AC:

152

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000151

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52562

Middle Eastern (MID)

AF:

0.00174

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.0000288

AC:

AN:

1111940

Other (OTH)

AF:

0.00351

AC:

212

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

126

252

379

505

631

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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

AF:

0.0166

AC:

2516

AN:

152004

Hom.:

Cov.:

AF XY:

0.0162

AC XY:

1201

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.0571

AC:

2359

AN:

41332

American (AMR)

AF:

0.00804

AC:

123

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

67996

Other (OTH)

AF:

0.00900

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

123

246

369

492

615

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0168

Hom.:

Bravo

AF:

0.0186

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

8.2

(source)

DANN

Benign

0.75

PhyloP100

-0.34

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over