NM_004913.3:c.1774G>T

Variant names:

• chr16-89708455-C-A
• rs372082040
• NM_004913.3:c.1774G>T

Variant summary

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

The NM_004913.3(VPS9D1):​c.1774G>T​(p.Ala592Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,390 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A592T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VPS9D1 NM_004913.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.69
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS9D1	NM_004913.3	c.1774G>T	p.Ala592Ser	missense_variant	Exon 14 of 15	ENST00000389386.8	NP_004904.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS9D1	ENST00000389386.8	c.1774G>T	p.Ala592Ser	missense_variant	Exon 14 of 15	1	NM_004913.3	ENSP00000374037.3
VPS9D1	ENST00000561976.5	c.1564G>T	p.Ala522Ser	missense_variant	Exon 13 of 14	1		ENSP00000454244.1
VPS9D1	ENST00000565023.1	c.574G>T	p.Ala192Ser	missense_variant	Exon 5 of 6	5		ENSP00000455792.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460390 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726488

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111804

Other (OTH) AF: 0.00 AC: 0 AN: 60344

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	.;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.50	D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.4	.;M
PhyloP100		5.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.77	N;N
REVEL	Benign	0.28
Sift	Benign	0.25	T;T
Sift4G	Uncertain	0.023	D;D
Polyphen		1.0	.;D
Vest4		0.56
MutPred		0.47		.;Gain of relative solvent accessibility (P = 0.0479);
MVP		0.69
MPC		0.23
ClinPred		0.97	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.49

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: rs372082040; hg19: chr16-89774863;