chr16-89710657-C-T

Variant names:

• chr16-89710657-C-T
• rs756169321
• NM_004913.3:c.1187G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004913.3(VPS9D1):​c.1187G>A​(p.Gly396Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: VPS9D1 NM_004913.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.116
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11887112).

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.1187G>A	p.Gly396Asp	missense	Exon 10 of 15	NP_004904.2	Q9Y2B5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS9D1	ENST00000389386.8	TSL:1 MANE Select	c.1187G>A	p.Gly396Asp	missense	Exon 10 of 15	ENSP00000374037.3	Q9Y2B5-1
	VPS9D1	ENST00000561976.5	TSL:1	c.977G>A	p.Gly326Asp	missense	Exon 9 of 14	ENSP00000454244.1	H3BM58
	VPS9D1	ENST00000906741.1		c.1187G>A	p.Gly396Asp	missense	Exon 10 of 15	ENSP00000576800.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000207 AC: 5 AN: 241492 AF XY: 0.0000226

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000168

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459478 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726066

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39680

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111596

Other (OTH) AF: 0.00 AC: 0 AN: 60214

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000249 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Benign	0.84
DEOGEN2	Benign	0.0091	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.12
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.021
Sift	Benign	0.21	T
Sift4G	Benign	0.24	T
Polyphen		0.84	P
Vest4		0.16
MutPred		0.29		Loss of methylation at R395 (P = 0.0313)
MVP		0.19
MPC		0.25
ClinPred		0.080	T
GERP RS		2.8
PromoterAI		0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.35
Mutation Taster		=97/3	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: rs756169321; hg19: chr16-89777065; COSMIC: COSV104700074; COSMIC: COSV104700074;