dbSNP rs769536879: VAC14:p.Asp777Tyr (chr16-70687948-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018052.5(VAC14):c.2329G>T(p.Asp777Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D777N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

VAC14
NM_018052.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.41

Publications

1 publications found

Variant links:

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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
hereditary neurological disease
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
Yunis-Varon syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

VAC14 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25235677).

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.2329G>T	p.Asp777Tyr	missense	Exon 19 of 19	NP_060522.3
	VAC14	NM_001351157.2		c.1627G>T	p.Asp543Tyr	missense	Exon 18 of 18	NP_001338086.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VAC14	ENST00000261776.10	TSL:1 MANE Select	c.2329G>T	p.Asp777Tyr	missense	Exon 19 of 19	ENSP00000261776.5	Q08AM6-1
VAC14	ENST00000568548.5	TSL:1	n.*2055G>T		non_coding_transcript_exon	Exon 18 of 18	ENSP00000454650.1	H3BN23
VAC14	ENST00000568886.5	TSL:1	n.*954G>T		non_coding_transcript_exon	Exon 13 of 13	ENSP00000457809.1	H3BUU8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000441

AC:

AN:

226982

AF XY:

0.00000812

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000963

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1419414

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

702104

African (AFR)

AF:

0.00

AC:

AN:

31868

American (AMR)

AF:

0.00

AC:

AN:

41284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24940

East Asian (EAS)

AF:

0.00

AC:

AN:

37380

South Asian (SAS)

AF:

0.00

AC:

AN:

81294

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52640

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4364

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1087346

Other (OTH)

AF:

0.00

AC:

AN:

58298

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.86

M_CAP

Benign

0.013

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.76

MutationAssessor

Benign

0.69

PhyloP100

7.4

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.7

REVEL

Benign

0.17

Sift

Uncertain

0.019

Sift4G

Uncertain

0.030

Polyphen

0.52

Vest4

0.54

MutPred

0.49

Gain of phosphorylation at D777 (P = 0.025)

MVP

0.068

MPC

1.1

ClinPred

0.77

GERP RS

5.4

Varity_R

0.32

gMVP

0.43

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over