rs749094914

chr16-70698729-C-Achr16-70698729-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP5

The NM_018052.5(VAC14):c.1744G>T(p.Ala582Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A582T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VAC14 NM_018052.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.56

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-70698729-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 808070.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
• PP5: Variant 16-70698729-C-A is Pathogenic according to our data. Variant chr16-70698729-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 253142.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VAC14	NM_018052.5	c.1744G>T	p.Ala582Ser	missense_variant	15/19	ENST00000261776.10
VAC14	NM_001351157.2	c.1042G>T	p.Ala348Ser	missense_variant	14/18
VAC14	XM_005256038.5	c.1744G>T	p.Ala582Ser	missense_variant	15/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAC14	ENST00000261776.10	c.1744G>T	p.Ala582Ser	missense_variant	15/19	1	NM_018052.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Striatonigral degeneration, childhood-onset Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 28, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Uncertain	-0.043	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.29
Sift	Benign	0.040	D;D
Sift4G	Uncertain	0.037	D;D
Polyphen		0.99	D;.
Vest4		0.73
MutPred		0.58		Gain of disorder (P = 0.0348);.;
MVP		0.22
MPC		1.2
ClinPred		0.92	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs749094914; hg19: chr16-70732632;