rs771231445

Variant names:

• chr16-89708885-C-T
• rs771231445
• NM_004913.3:c.1669G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004913.3(VPS9D1):​c.1669G>A​(p.Gly557Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000504 in 1,587,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: VPS9D1 NM_004913.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.779
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05695808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS9D1	NM_004913.3	c.1669G>A	p.Gly557Arg	missense_variant	Exon 13 of 15	ENST00000389386.8	NP_004904.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS9D1	ENST00000389386.8	c.1669G>A	p.Gly557Arg	missense_variant	Exon 13 of 15	1	NM_004913.3	ENSP00000374037.3
VPS9D1	ENST00000561976.5	c.1459G>A	p.Gly487Arg	missense_variant	Exon 12 of 14	1		ENSP00000454244.1
VPS9D1	ENST00000565023.1	c.469G>A	p.Gly157Arg	missense_variant	Exon 4 of 6	5		ENSP00000455792.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152202 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000855 AC: 18 AN: 210432 AF XY: 0.0000772

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000762

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000630

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000143

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000481 AC: 69 AN: 1435468 Hom.: 0 Cov.: 33 AF XY: 0.0000574 AC XY: 41 AN XY: 713776

African (AFR) AF: 0.00 AC: 0 AN: 31954

American (AMR) AF: 0.000110 AC: 4 AN: 36416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24836

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39476

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5472

European-Non Finnish (NFE) AF: 0.0000543 AC: 60 AN: 1104900

Other (OTH) AF: 0.0000507 AC: 3 AN: 59180

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152202 Hom.: 0 Cov.: 34 AF XY: 0.000121 AC XY: 9 AN XY: 74358

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.000262 AC: 4 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000149 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.0000585 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1669G>A (p.G557R) alteration is located in exon 13 (coding exon 13) of the VPS9D1 gene. This alteration results from a G to A substitution at nucleotide position 1669, causing the glycine (G) at amino acid position 557 to be replaced by an arginine (R). 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	0.10
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	13
DANN	Benign	0.72
DEOGEN2	Benign	0.018	.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.49	T;T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.057	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.26	.;N
PhyloP100		0.78
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.98	N;N
REVEL	Benign	0.020
Sift	Benign	0.17	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.015	.;B
Vest4		0.061
MutPred		0.42		.;Gain of solvent accessibility (P = 0.0037);
MVP		0.12
MPC		0.22
ClinPred		0.018	T
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.058
gMVP		0.23
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs771231445; hg19: chr16-89775293;