NM_018052.5:c.1339C>G

Variant names:

• chr16-70762572-G-C
• rs1210703688
• NM_018052.5:c.1339C>G

Variant summary

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

The NM_018052.5(VAC14):​c.1339C>G​(p.Leu447Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VAC14 NM_018052.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.00
• Publications: 0 publications found

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]

VAC14-AS1 (HGNC:48605): (VAC14 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018052.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAC14	NM_018052.5	MANE Select	c.1339C>G	p.Leu447Val	missense	Exon 12 of 19	NP_060522.3
	VAC14	NM_001351157.2		c.637C>G	p.Leu213Val	missense	Exon 11 of 18	NP_001338086.1
	VAC14-AS1	NR_034083.3		n.336+1314G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAC14	ENST00000261776.10	TSL:1 MANE Select	c.1339C>G	p.Leu447Val	missense	Exon 12 of 19	ENSP00000261776.5	Q08AM6-1
	VAC14	ENST00000568548.5	TSL:1	n.*1065C>G		non_coding_transcript_exon	Exon 11 of 18	ENSP00000454650.1	H3BN23
	VAC14	ENST00000568886.5	TSL:1	n.570C>G		non_coding_transcript_exon	Exon 6 of 13	ENSP00000457809.1	H3BUU8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Striatonigral degeneration, childhood-onset (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.045	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.0
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.60
Sift	Benign	0.095	T
Sift4G	Benign	0.064	T
Polyphen		0.99	D
Vest4		0.82
MutPred		0.45		Gain of catalytic residue at L447 (P = 0.2068)
MVP		0.50
MPC		1.2
ClinPred		0.94	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.64

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: rs1210703688; hg19: chr16-70796475;