16-89711882-A-T

Variant names:

• chr16-89711882-A-T
• rs201251363
• NM_004913.3:c.747T>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004913.3(VPS9D1):​c.747T>A​(p.His249Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VPS9D1 NM_004913.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.72

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]

VPS9D1-AS1 (HGNC:48915): (VPS9D1 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39463693).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS9D1	NM_004913.3	c.747T>A	p.His249Gln	missense_variant, splice_region_variant	Exon 8 of 15	ENST00000389386.8	NP_004904.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS9D1	ENST00000389386.8	c.747T>A	p.His249Gln	missense_variant, splice_region_variant	Exon 8 of 15	1	NM_004913.3	ENSP00000374037.3
VPS9D1	ENST00000561976.5	c.537T>A	p.His179Gln	missense_variant, splice_region_variant	Exon 7 of 14	1		ENSP00000454244.1
VPS9D1	ENST00000563798.1	n.*256T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 6	3		ENSP00000454889.1
VPS9D1	ENST00000563798.1	n.*256T>A		3_prime_UTR_variant	Exon 5 of 6	3		ENSP00000454889.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1398324 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 689704

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.2
DANN	Benign	0.95
DEOGEN2	Benign	0.35	.;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	.;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.019	D;D
Polyphen		1.0	.;D
Vest4		0.58
MutPred		0.21		.;Gain of solvent accessibility (P = 0.0155);
MVP		0.25
MPC		0.48
ClinPred		0.99	D
GERP RS		-4.3
Varity_R		0.35
gMVP		0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs201251363; hg19: chr16-89778290;