16-89711957-G-C

Variant names:

• chr16-89711957-G-C
• rs1044172676
• NM_004913.3:c.672C>G

Variant summary

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

The NM_004913.3(VPS9D1):​c.672C>G​(p.Ser224Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VPS9D1 NM_004913.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19936591).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS9D1	NM_004913.3	c.672C>G	p.Ser224Arg	missense_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.672C>G	p.Ser224Arg	missense_variant	Exon 8 of 15	1	NM_004913.3	ENSP00000374037.3
VPS9D1	ENST00000561976.5	c.462C>G	p.Ser154Arg	missense_variant	Exon 7 of 14	1		ENSP00000454244.1
VPS9D1	ENST00000563798.1	n.*181C>G		non_coding_transcript_exon_variant	Exon 5 of 6	3		ENSP00000454889.1
VPS9D1	ENST00000563798.1	n.*181C>G		3_prime_UTR_variant	Exon 5 of 6	3		ENSP00000454889.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1398766 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 689972

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: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.672C>G (p.S224R) alteration is located in exon 8 (coding exon 8) of the VPS9D1 gene. This alteration results from a C to G substitution at nucleotide position 672, causing the serine (S) at amino acid position 224 to be replaced by an arginine (R). 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	Pathogenic	0.68
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	.;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	.;M
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.13
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.037	D;D
Polyphen		0.84	.;P
Vest4		0.48
MutPred		0.29		.;Gain of solvent accessibility (P = 0.0055);
MVP		0.28
MPC		0.57
ClinPred		0.96	D
GERP RS		-1.2
Varity_R		0.34
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1044172676; hg19: chr16-89778365;