chr16-70744422-C-T

Variant names:

• chr16-70744422-C-T
• rs879255555
• NM_018052.5:c.1528+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_018052.5(VAC14):​c.1528+1G>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: VAC14 NM_018052.5 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.11
• 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 Gene-Disease associations (from GenCC):

• striatonigral degeneration, childhood-onset

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary neurological disease

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• Yunis-Varon syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000260156 (HGNC:58481):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.8, offset of -40, new splice context is: cagGTgccc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-70744422-C-T is Pathogenic according to our data. Variant chr16-70744422-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 253141.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAC14	NM_018052.5	MANE Select	c.1528+1G>A		splice_donor intron	N/A	NP_060522.3
	VAC14	NM_001351157.2		c.826+1G>A		splice_donor intron	N/A	NP_001338086.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAC14	ENST00000261776.10	TSL:1 MANE Select	c.1528+1G>A		splice_donor intron	N/A	ENSP00000261776.5
	VAC14	ENST00000564685.5	TSL:1	n.216+1G>A		splice_donor intron	N/A
	VAC14	ENST00000568548.5	TSL:1	n.*1254+1G>A		splice_donor intron	N/A	ENSP00000454650.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Jul 28, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	32
DANN	Benign	0.97
Eigen	Pathogenic	0.82
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		5.1
GERP RS		5.4
PromoterAI		-0.27	Neutral
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.67		Position offset: 41
DS_DL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs879255555; hg19: chr16-70778325;