16-89720779-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004913.3(VPS9D1):c.83C>G(p.Thr28Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000767 in 1,303,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: VPS9D1 NM_004913.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43

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]

ZNF276 (HGNC:23330): (zinc finger protein 276) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in kinetochore. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16052482).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS9D1	NM_004913.3	c.83C>G	p.Thr28Ser	missense_variant	1/15	ENST00000389386.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS9D1	ENST00000389386.8	c.83C>G	p.Thr28Ser	missense_variant	1/15	1	NM_004913.3	A2
VPS9D1	ENST00000563798.1	c.83C>G	p.Thr28Ser	missense_variant, NMD_transcript_variant	1/6	3
ZNF276	ENST00000562530.5	c.-21+197G>C		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.67e-7 AC: 1 AN: 1303768 Hom.: 0 Cov.: 32 AF XY: 0.00000156 AC XY: 1 AN XY: 642978

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: 0.0000143

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2023

The c.83C>G (p.T28S) alteration is located in exon 1 (coding exon 1) of the VPS9D1 gene. This alteration results from a C to G substitution at nucleotide position 83, causing the threonine (T) at amino acid position 28 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	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	19
Dann	Benign	0.90
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.93	N;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.025
Sift	Benign	0.31	T
Sift4G	Benign	0.59	T
Polyphen		0.018	B
Vest4		0.058
MutPred		0.14		Gain of disorder (P = 0.0486);
MVP		0.088
MPC		0.48
ClinPred		0.23	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.081
gMVP		0.075

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

Publications

LitVar

Other links and lift over

dbSNP: rs2061242996; hg19: chr16-89787187;