rs1597963648

Variant names:

• chr16-70762554-C-A
• rs1597963648
• NM_018052.5:c.1357G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_018052.5(VAC14):​c.1357G>T​(p.Asp453Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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, single submitter U:1
• Conservation: PhyloP100: 7.07
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926

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.1357G>T	p.Asp453Tyr	missense	Exon 12 of 19	NP_060522.3
	VAC14	NM_001351157.2		c.655G>T	p.Asp219Tyr	missense	Exon 11 of 18	NP_001338086.1
	VAC14-AS1	NR_034083.3		n.336+1296C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAC14	ENST00000261776.10	TSL:1 MANE Select	c.1357G>T	p.Asp453Tyr	missense	Exon 12 of 19	ENSP00000261776.5	Q08AM6-1
	VAC14	ENST00000568548.5	TSL:1	n.*1083G>T		non_coding_transcript_exon	Exon 11 of 18	ENSP00000454650.1	H3BN23
	VAC14	ENST00000568886.5	TSL:1	n.588G>T		non_coding_transcript_exon	Exon 6 of 13	ENSP00000457809.1	H3BUU8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.1
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Uncertain	0.59
Sift	Benign	0.035	D
Sift4G	Uncertain	0.035	D
Polyphen		0.99	D
Vest4		0.93
MutPred		0.58		Loss of disorder (P = 0.0172)
MVP		0.55
MPC		1.4
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.88

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: rs1597963648; hg19: chr16-70796457;