20-23397131-T-C

Variant names:

• chr20-23397131-T-C
• rs527669105
• ENST00000398425.7:c.1A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_001283026.2(NAPB):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,506 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NAPB NM_001283026.2 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.01
• Publications: 0 publications found

Genes affected

NAPB (HGNC:15751): (NSF attachment protein beta) This gene encodes a member of the soluble N-ethyl-maleimide-sensitive fusion 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. This gene encodes the SNAP beta isoform which has been shown to be preferentially expressed in brain tissue. The encoded protein also interacts with the GluR2 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor subunit C-terminus and may play a role as a chaperone in the molecular processing of the AMPA receptor. [provided by RefSeq, Mar 2017]

NAPB Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy 107

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 9 codons. Genomic position: 23397107. Lost 0.041 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001283026.2. 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
	NAPB	NM_022080.3	MANE Select	c.236A>G	p.His79Arg	missense	Exon 3 of 11	NP_071363.1	Q9H115-1
	NAPB	NM_001283026.2		c.1A>G	p.Met1?	start_lost	Exon 3 of 10	NP_001269955.1	Q9H115-3
	NAPB	NM_001283018.2		c.248A>G	p.His83Arg	missense	Exon 3 of 11	NP_001269947.1	A0A087WZQ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAPB	ENST00000398425.7	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 3 of 10	ENSP00000381459.3	Q9H115-3
	NAPB	ENST00000377026.4	TSL:1 MANE Select	c.236A>G	p.His79Arg	missense	Exon 3 of 11	ENSP00000366225.4	Q9H115-1
	NAPB	ENST00000617876.4	TSL:2	c.248A>G	p.His83Arg	missense	Exon 3 of 11	ENSP00000482826.1	A0A087WZQ7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461506 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727050

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111722

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.29	T
PhyloP100		8.0
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.2	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.90	P
Vest4		0.72
MutPred		0.35		Gain of MoRF binding (P = 0.0507)
MVP		0.58
MPC		1.0
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.89
gMVP		0.63
Mutation Taster		=79/121	disease causing

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: rs527669105; hg19: chr20-23377768;