19-47495570-T-G

Variant names:

• chr19-47495570-T-G
• rs777333925
• NM_003827.4:c.322A>C

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.01
• Publications: 0 publications found

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

ACMG classification

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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

Sel.	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.: 0 Cov.: 31

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: 23 AN: 250698 AF XY: 0.000118

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.: 0 Cov.: 31 AF XY: 0.0129 AC XY: 8674 AN XY: 674830

⚠️ 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: 61 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.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0172 AC: 2150 AN: 125284 Hom.: 0 Cov.: 31 AF XY: 0.0183 AC XY: 1114 AN XY: 60876

⚠️ 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: 24 AN: 2818

East Asian (EAS) AF: 0.0126 AC: 57 AN: 4528

South Asian (SAS) AF: 0.0107 AC: 45 AN: 4192

European-Finnish (FIN) AF: 0.00873 AC: 81 AN: 9280

Middle Eastern (MID) AF: 0.00840 AC: 2 AN: 238

European-Non Finnish (NFE) AF: 0.0156 AC: 876 AN: 56308

Other (OTH) AF: 0.0241 AC: 40 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.

Alfa AF: 0.00232 Hom.: 0

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	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.021
Eigen_PC	Benign	0.045
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		8.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.055	T
Polyphen		0.0030	B
Vest4		0.81
MutPred		0.56		Loss of MoRF binding (P = 0.3087)
MVP		0.89
MPC		0.41
ClinPred		0.14	T
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

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

Other links and lift over

dbSNP: rs777333925; hg19: chr19-47998827;