NM_130811.4:c.4G>A

Variant names:

• chr20-10275495-G-A
• rs769950821
• NM_130811.4:c.4G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_130811.4(SNAP25):​c.4G>A​(p.Ala2Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,451,272 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SNAP25 NM_130811.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.20
• Publications: 0 publications found

Genes affected

SNAP25 (HGNC:11132): (synaptosome associated protein 25) Synaptic vesicle membrane docking and fusion is mediated by SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) located on the vesicle membrane (v-SNAREs) and the target membrane (t-SNAREs). The assembled v-SNARE/t-SNARE complex consists of a bundle of four helices, one of which is supplied by v-SNARE and the other three by t-SNARE. For t-SNAREs on the plasma membrane, the protein syntaxin supplies one helix and the protein encoded by this gene contributes the other two. Therefore, this gene product is a presynaptic plasma membrane protein involved in the regulation of neurotransmitter release. Two alternative transcript variants encoding different protein isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

SNAP25-AS1 (HGNC:44312): (SNAP25 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130811.4. 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
	SNAP25	NM_130811.4	MANE Select	c.4G>A	p.Ala2Thr	missense	Exon 2 of 8	NP_570824.1	P60880-1
	SNAP25	NM_001322902.2		c.4G>A	p.Ala2Thr	missense	Exon 2 of 8	NP_001309831.1	P60880-2
	SNAP25	NM_001322903.2		c.4G>A	p.Ala2Thr	missense	Exon 3 of 9	NP_001309832.1	P60880-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNAP25	ENST00000254976.7	TSL:1 MANE Select	c.4G>A	p.Ala2Thr	missense	Exon 2 of 8	ENSP00000254976.3	P60880-1
	SNAP25	ENST00000304886.6	TSL:1	c.4G>A	p.Ala2Thr	missense	Exon 2 of 8	ENSP00000307341.2	P60880-2
	SNAP25	ENST00000961779.1		c.4G>A	p.Ala2Thr	missense	Exon 2 of 9	ENSP00000631838.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1451272 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 720920

African (AFR) AF: 0.00 AC: 0 AN: 33354

American (AMR) AF: 0.00 AC: 0 AN: 43554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25864

East Asian (EAS) AF: 0.00 AC: 0 AN: 39448

South Asian (SAS) AF: 0.00 AC: 0 AN: 83888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106672

Other (OTH) AF: 0.00 AC: 0 AN: 60016

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital myasthenic syndrome 18 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0057	T
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.8	L
PhyloP100		9.2
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.27
Sift	Benign	0.16	T
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.70
MutPred		0.13		Gain of phosphorylation at A2 (P = 0.0054)
MVP		0.34
MPC		0.44
ClinPred		0.96	D
GERP RS		6.1
Varity_R		0.27
gMVP		0.66
Mutation Taster		=48/52	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: rs769950821; hg19: chr20-10256143;