Genetic Variant NAPA:p.Ile108Val (chr19-47495570-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003827.4(NAPA):c.322A>G(p.Ile108Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000612 in 1,601,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000035 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

NAPA
NM_003827.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.01

Variant links:

Genes affected

NAPA (HGNC:7641): (NSF attachment protein alpha) This gene encodes a member of the soluble NSF attachment protein (SNAP) family. SNAP proteins play a critical role in the docking and fusion of vesicles to target membranes as part of the 20S NSF-SNAP-SNARE complex. The encoded protein plays a role in the completion of membrane fusion by mediating the interaction of N-ethylmaleimide-sensitive factor (NSF) with the vesicle-associated and membrane-associated SNAP receptor (SNARE) complex, and stimulating the ATPase activity of NSF. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Jun 2011]

NAPA links:

NAPA-AS1 (HGNC:44118): (NAPA antisense RNA 1)

NAPA-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2593234).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAPA	NM_003827.4 link	c.322A>G	p.Ile108Val	missense_variant	Exon 4 of 11	ENST00000263354.8	NP_003818.2	P54920A0A024R0R9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAPA	ENST00000263354.8 link	c.322A>G	p.Ile108Val	missense_variant	Exon 4 of 11	1	NM_003827.4	ENSP00000263354.2		P54920

Frequencies

GnomAD3 genomes

AF:

0.0000349

AC:

AN:

143456

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000769

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000439

AC:

AN:

250698

Hom.:

AF XY:

0.0000664

AC XY:

AN XY:

135488

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000705

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000638

AC:

AN:

1457652

Hom.:

Cov.:

AF XY:

0.0000621

AC XY:

AN XY:

724752

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000674

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000766

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.0000349

AC:

AN:

143456

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69676

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000769

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000820

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 19, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.322A>G (p.I108V) alteration is located in exon 4 (coding exon 4) of the NAPA gene. This alteration results from a A to G substitution at nucleotide position 322, causing the isoleucine (I) at amino acid position 108 to be replaced by a valine (V). 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

Benign

0.079

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.088

T;T;.;.;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

D;D;D;D;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.26

T;T;T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.49

N;.;.;.;.

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.32

N;.;.;.;.

REVEL

Benign

0.22

Sift

Benign

0.67

T;.;.;.;.

Sift4G

Benign

0.39

T;T;.;.;T

Polyphen

0.0010

B;.;.;.;.

Vest4

0.64

MutPred

0.60

Gain of MoRF binding (P = 0.2776);.;.;.;.;

MVP

0.60

MPC

0.23

ClinPred

0.14

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.035

gMVP

0.23

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over