Genetic Variant NM_003827.4:c.322A>C (chr19-47495570-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_003827.4(NAPA):c.322A>C(p.Ile108Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 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. I108V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.017 ( 0 hom., cov: 31)

Exomes 𝑓: 0.012 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NAPA
NM_003827.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.01

Publications

0 publications found

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 was made for transcript

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003827.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NAPA	NM_003827.4	MANE Select	c.322A>C	p.Ile108Leu	missense	Exon 4 of 11	NP_003818.2
NAPA	NR_038456.2		n.445A>C		non_coding_transcript_exon	Exon 4 of 12
NAPA	NR_038457.2		n.248A>C		non_coding_transcript_exon	Exon 2 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NAPA	ENST00000263354.8	TSL:1 MANE Select	c.322A>C	p.Ile108Leu	missense	Exon 4 of 11	ENSP00000263354.2	P54920
NAPA	ENST00000595826.5	TSL:1	n.530A>C		non_coding_transcript_exon	Exon 5 of 7
NAPA	ENST00000602082.5	TSL:1	n.207A>C		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

2150

AN:

125158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0202

Gnomad AMI

AF:

0.0102

Gnomad AMR

AF:

0.0291

Gnomad ASJ

AF:

0.00852

Gnomad EAS

AF:

0.0126

Gnomad SAS

AF:

0.0107

Gnomad FIN

AF:

0.00873

Gnomad MID

AF:

0.00800

Gnomad NFE

AF:

0.0156

Gnomad OTH

AF:

0.0245

GnomAD2 exomes

AF:

0.0000917

AC:

AN:

250698

AF XY:

0.000118

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000705

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0125

AC:

17076

AN:

1368184

Hom.:

Cov.:

AF XY:

0.0129

AC XY:

8674

AN XY:

674830

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0198

AC:

620

AN:

31346

American (AMR)

AF:

0.0251

AC:

1001

AN:

39826

Ashkenazi Jewish (ASJ)

AF:

0.0152

AC:

368

AN:

24188

East Asian (EAS)

AF:

0.0251

AC:

914

AN:

36396

South Asian (SAS)

AF:

0.0358

AC:

2353

AN:

65676

European-Finnish (FIN)

AF:

0.0122

AC:

597

AN:

49060

Middle Eastern (MID)

AF:

0.0112

AC:

AN:

5462

European-Non Finnish (NFE)

AF:

0.00969

AC:

10273

AN:

1060320

Other (OTH)

AF:

0.0159

AC:

889

AN:

55910

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.240

Heterozygous variant carriers

2804

5608

8411

11215

14019

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

240

360

480

600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0172

AC:

2150

AN:

125284

Hom.:

Cov.:

AF XY:

0.0183

AC XY:

1114

AN XY:

60876

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0201

AC:

687

AN:

34128

American (AMR)

AF:

0.0291

AC:

330

AN:

11346

Ashkenazi Jewish (ASJ)

AF:

0.00852

AC:

AN:

2818

East Asian (EAS)

AF:

0.0126

AC:

AN:

4528

South Asian (SAS)

AF:

0.0107

AC:

AN:

4192

European-Finnish (FIN)

AF:

0.00873

AC:

AN:

9280

Middle Eastern (MID)

AF:

0.00840

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0156

AC:

876

AN:

56308

Other (OTH)

AF:

0.0241

AC:

AN:

1658

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.246

Heterozygous variant carriers

325

650

976

1301

1626

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00232

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.18

Eigen

Benign

0.021

Eigen_PC

Benign

0.045

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.068

MetaRNN

Uncertain

0.56

MetaSVM

Uncertain

-0.19

MutationAssessor

Pathogenic

3.0

PhyloP100

8.0

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.44

Sift

Uncertain

0.025

Sift4G

Uncertain

0.055

Polyphen

0.0030

Vest4

0.81

MutPred

0.56

Loss of MoRF binding (P = 0.3087)

MVP

0.89

MPC

0.41

ClinPred

0.14

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.22

gMVP

0.56

Mutation Taster

=70/30

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over