16-89708935-C-G

Variant names:

• chr16-89708935-C-G
• NM_004913.3:c.1619G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004913.3(VPS9D1):​c.1619G>C​(p.Cys540Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: VPS9D1 NM_004913.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.49
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS9D1	NM_004913.3	c.1619G>C	p.Cys540Ser	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.1619G>C	p.Cys540Ser	missense_variant	Exon 13 of 15	1	NM_004913.3	ENSP00000374037.3
VPS9D1	ENST00000561976.5	c.1409G>C	p.Cys470Ser	missense_variant	Exon 12 of 14	1		ENSP00000454244.1
VPS9D1	ENST00000565023.1	c.419G>C	p.Cys140Ser	missense_variant	Exon 4 of 6	5		ENSP00000455792.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1619G>C (p.C540S) alteration is located in exon 13 (coding exon 13) of the VPS9D1 gene. This alteration results from a G to C substitution at nucleotide position 1619, causing the cysteine (C) at amino acid position 540 to be replaced by a serine (S). 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	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.069	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	.;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.86	D;D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.5	.;M
PhyloP100		4.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Uncertain	0.34
Sift	Benign	0.054	T;T
Sift4G	Uncertain	0.058	T;T
Polyphen		1.0	.;D
Vest4		0.81
MutPred		0.66		.;Loss of sheet (P = 0.0126);
MVP		0.58
MPC		0.64
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.48
gMVP		0.53

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

Other links and lift over

hg19: chr16-89775343;