15-42513445-A-G

Variant names:

• chr15-42513445-A-G
• NM_003825.4:c.146A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003825.4(SNAP23):​c.146A>G​(p.Lys49Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SNAP23 NM_003825.4 missense, splice_region
• Scores: Splicing: ADA: 0.03418
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.88

Genes affected

SNAP23 (HGNC:11131): (synaptosome associated protein 23) Specificity of vesicular transport is regulated, in part, by the interaction of a vesicle-associated membrane protein termed synaptobrevin/VAMP with a target compartment membrane protein termed syntaxin. These proteins, together with SNAP25 (synaptosome-associated protein of 25 kDa), form a complex which serves as a binding site for the general membrane fusion machinery. Synaptobrevin/VAMP and syntaxin are believed to be involved in vesicular transport in most, if not all cells, while SNAP25 is present almost exclusively in the brain, suggesting that a ubiquitously expressed homolog of SNAP25 exists to facilitate transport vesicle/target membrane fusion in other tissues. The protein encoded by this gene is structurally and functionally similar to SNAP25 and binds tightly to multiple syntaxins and synaptobrevins/VAMPs. It is an essential component of the high affinity receptor for the general membrane fusion machinery and is an important regulator of transport vesicle docking and fusion. Two alternative transcript variants encoding different protein isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

ENSG00000285942 (HGNC:):

ACMG classification

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=0.19323123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNAP23	NM_003825.4	c.146A>G	p.Lys49Arg	missense_variant, splice_region_variant	Exon 4 of 8	ENST00000249647.8	NP_003816.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNAP23	ENST00000249647.8	c.146A>G	p.Lys49Arg	missense_variant, splice_region_variant	Exon 4 of 8	1	NM_003825.4	ENSP00000249647.3
ENSG00000285942	ENST00000650210.1	n.*310+1678T>C		intron_variant	Intron 8 of 8			ENSP00000497618.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.146A>G (p.K49R) alteration is located in exon 4 (coding exon 3) of the SNAP23 gene. This alteration results from a A to G substitution at nucleotide position 146, causing the lysine (K) at amino acid position 49 to be replaced by an arginine (R). 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	0.078
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	T;T;.;T;.;T;.;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.053
FATHMM_MKL	Benign	0.095	N
LIST_S2	Uncertain	0.93	D;D;D;D;.;D;D;.
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N;N;.;.;.;.;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.10	N;N;N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.026	D;D;D;T;D;D;D;D
Polyphen		0.010, 0.0010	.;B;B;.;.;.;.;B
Vest4		0.18, 0.20, 0.17, 0.19, 0.19
MutPred		0.45		Loss of ubiquitination at K49 (P = 0.0077);Loss of ubiquitination at K49 (P = 0.0077);Loss of ubiquitination at K49 (P = 0.0077);Loss of ubiquitination at K49 (P = 0.0077);Loss of ubiquitination at K49 (P = 0.0077);.;Loss of ubiquitination at K49 (P = 0.0077);Loss of ubiquitination at K49 (P = 0.0077);
MVP		0.29
MPC		0.25
ClinPred		0.85	D
GERP RS		4.6
Varity_R		0.62
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.034
dbscSNV1_RF	Benign	0.27
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-42805643;