18-9914328-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_194434.3(VAPA):c.72A>C(p.Lys24Asn) 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: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: VAPA NM_194434.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86

Genes affected

VAPA (HGNC:12648): (VAMP associated protein A) The protein encoded by this gene is a type IV membrane protein. It is present in the plasma membrane and intracellular vesicles. It may also be associated with the cytoskeleton. This protein may function in vesicle trafficking, membrane fusion, protein complex assembly and cell motility. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VAPA	NM_194434.3	c.72A>C	p.Lys24Asn	missense_variant	1/6	ENST00000400000.7
VAPA	NM_003574.6	c.72A>C	p.Lys24Asn	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAPA	ENST00000400000.7	c.72A>C	p.Lys24Asn	missense_variant	1/6	1	NM_194434.3	P1
VAPA	ENST00000340541.4	c.72A>C	p.Lys24Asn	missense_variant	1/7	5
VAPA	ENST00000577901.5	n.277A>C		non_coding_transcript_exon_variant	1/3	2
VAPA	ENST00000585042.5	c.72A>C	p.Lys24Asn	missense_variant, NMD_transcript_variant	1/4	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1427906 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 710272

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2023

The c.72A>C (p.K24N) alteration is located in exon 1 (coding exon 1) of the VAPA gene. This alteration results from a A to C substitution at nucleotide position 72, causing the lysine (K) at amino acid position 24 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
Cadd	Uncertain	25
Dann	Benign	0.93
DEOGEN2	Uncertain	0.63	D;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.40	N
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.7	D;D
REVEL	Benign	0.23
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.031	D;D
Polyphen		0.0020	B;B
Vest4		0.36
MutPred		0.51		Loss of methylation at K24 (P = 0.02);Loss of methylation at K24 (P = 0.02);
MVP		0.77
MPC		1.2
ClinPred		0.98	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.66

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

LitVar

Other links and lift over

dbSNP: rs1449189820; hg19: chr18-9914325;