16-70687962-C-A

Variant names:

• chr16-70687962-C-A
• rs763889868
• NM_018052.5:c.2315G>T

Variant summary

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

The NM_018052.5(VAC14):​c.2315G>T​(p.Arg772Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,434,758 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: 34)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: VAC14 NM_018052.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.85

Genes affected

VAC14 (HGNC:25507): (VAC14 component of PIKFYVE complex) This gene encodes a scaffold protein that is a component of the PIKfyve protein kinase complex. This complex is responsible for the synthesis of phosphatidylinositol 3,5-bisphosphate, an important component of cellular membranes, from phosphatidylinositol 3-phosphate. Mice lacking a functional copy of this gene exhibit severe neurodegeneration. Mutations in the human gene have been identified in patients with a childhood onset progressive neurological disorder characterized by impaired movement, dystonia, and striatal abnormalities. [provided by RefSeq, May 2017]

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=0.1917744).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAC14	NM_018052.5	c.2315G>T	p.Arg772Leu	missense_variant	Exon 19 of 19	ENST00000261776.10	NP_060522.3
VAC14	NM_001351157.2	c.1613G>T	p.Arg538Leu	missense_variant	Exon 18 of 18		NP_001338086.1
VAC14	XM_005256038.5	c.*3901G>T		3_prime_UTR_variant	Exon 19 of 19		XP_005256095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAC14	ENST00000261776.10	c.2315G>T	p.Arg772Leu	missense_variant	Exon 19 of 19	1	NM_018052.5	ENSP00000261776.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1434758 Hom.: 0 Cov.: 29 AF XY: 0.00000141 AC XY: 1 AN XY: 711346

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: 9.12e-7

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

Inborn genetic diseases Uncertain:1

Mar 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2315G>T (p.R772L) alteration is located in exon 19 (coding exon 19) of the VAC14 gene. This alteration results from a G to T substitution at nucleotide position 2315, causing the arginine (R) at amino acid position 772 to be replaced by a leucine (L). 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	0.18
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	0.091
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.97	L;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0090	D;T
Sift4G	Benign	0.16	T;T
Polyphen		0.36	B;.
Vest4		0.40
MutPred		0.29		Loss of MoRF binding (P = 0.0071);.;
MVP		0.10
MPC		0.69
ClinPred		0.87	D
GERP RS		5.4
Varity_R		0.40
gMVP		0.41

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: rs763889868; hg19: chr16-70721865;