16-89709418-C-T

Variant names:

• chr16-89709418-C-T
• rs768244692
• NM_004913.3:c.1406G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004913.3(VPS9D1):​c.1406G>A​(p.Arg469Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000672 in 1,516,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: VPS9D1 NM_004913.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.798
• Publications: 1 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06628153).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS9D1	NM_004913.3	c.1406G>A	p.Arg469Gln	missense_variant	Exon 12 of 15	ENST00000389386.8	NP_004904.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS9D1	ENST00000389386.8	c.1406G>A	p.Arg469Gln	missense_variant	Exon 12 of 15	1	NM_004913.3	ENSP00000374037.3
VPS9D1	ENST00000561976.5	c.1196G>A	p.Arg399Gln	missense_variant	Exon 11 of 14	1		ENSP00000454244.1
VPS9D1	ENST00000565023.1	c.206G>A	p.Arg69Gln	missense_variant	Exon 3 of 6	5		ENSP00000455792.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152118 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000859 AC: 14 AN: 162900 AF XY: 0.000114

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000461

Gnomad ASJ exome AF: 0.000296

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000718 AC: 98 AN: 1364524 Hom.: 0 Cov.: 32 AF XY: 0.0000999 AC XY: 67 AN XY: 670428

African (AFR) AF: 0.00 AC: 0 AN: 30534

American (AMR) AF: 0.0000324 AC: 1 AN: 30870

Ashkenazi Jewish (ASJ) AF: 0.0000496 AC: 1 AN: 20178

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38926

South Asian (SAS) AF: 0.000950 AC: 68 AN: 71590

European-Finnish (FIN) AF: 0.0000250 AC: 1 AN: 39998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3960

European-Non Finnish (NFE) AF: 0.0000205 AC: 22 AN: 1072150

Other (OTH) AF: 0.0000710 AC: 4 AN: 56318

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152236 Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3 AN XY: 74422

African (AFR) AF: 0.00 AC: 0 AN: 41542

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.000119 AC: 14

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1406G>A (p.R469Q) alteration is located in exon 12 (coding exon 12) of the VPS9D1 gene. This alteration results from a G to A substitution at nucleotide position 1406, causing the arginine (R) at amino acid position 469 to be replaced by a glutamine (Q). 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	0.087
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	.;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.066	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	.;L
PhyloP100		0.80
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.033
Sift	Benign	0.16	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.23	.;B
Vest4		0.32
MutPred		0.44		.;Loss of MoRF binding (P = 0.0458);
MVP		0.25
MPC		0.21
ClinPred		0.092	T
GERP RS		2.1
Varity_R		0.070
gMVP		0.37
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs768244692; hg19: chr16-89775826;