chr16-89709371-G-A

Variant names:

• chr16-89709371-G-A
• rs2060863971
• NM_004913.3:c.1453C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004913.3(VPS9D1):​c.1453C>T​(p.Pro485Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000705 in 1,418,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P485A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: VPS9D1 NM_004913.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.64
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.747

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS9D1	NM_004913.3	c.1453C>T	p.Pro485Ser	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.1453C>T	p.Pro485Ser	missense_variant	Exon 12 of 15	1	NM_004913.3	ENSP00000374037.3
VPS9D1	ENST00000561976.5	c.1243C>T	p.Pro415Ser	missense_variant	Exon 11 of 14	1		ENSP00000454244.1
VPS9D1	ENST00000565023.1	c.253C>T	p.Pro85Ser	missense_variant	Exon 3 of 6	5		ENSP00000455792.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1418678 Hom.: 0 Cov.: 32 AF XY: 0.00000142 AC XY: 1 AN XY: 702614

African (AFR) AF: 0.00 AC: 0 AN: 32578

American (AMR) AF: 0.00 AC: 0 AN: 40812

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22994

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39552

South Asian (SAS) AF: 0.00 AC: 0 AN: 79552

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094520

Other (OTH) AF: 0.00 AC: 0 AN: 58772

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	.;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Pathogenic	3.1	.;M
PhyloP100		4.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Benign	0.26
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.020	D;D
Polyphen		1.0	.;D
Vest4		0.72
MutPred		0.46		.;Gain of relative solvent accessibility (P = 0.0483);
MVP		0.44
MPC		0.49
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.34
gMVP		0.60

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: rs2060863971; hg19: chr16-89775779; COSMIC: COSV107493596; COSMIC: COSV107493596;