rs79020892

chr20-10306125-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_130811.4(SNAP25):c.553-4C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,613,448 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (77 hom., cov: 30)
  • Exomes 𝑓: 0.0019 (55 hom.)
• Consequence: SNAP25 NM_130811.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0004871
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.445

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 20-10306125-C-T is Benign according to our data. Variant chr20-10306125-C-T is described in ClinVar as [Benign]. Clinvar id is 476115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNAP25	NM_130811.4	c.553-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000254976.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNAP25	ENST00000254976.7	c.553-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_130811.4	P5
SNAP25-AS1	ENST00000421143.6	n.5+62590G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2511 AN: 151952 Hom.: 77 Cov.: 30

Gnomad AFR AF: 0.0565

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00767

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00426 AC: 1069 AN: 251166 Hom.: 24 AF XY: 0.00345 AC XY: 468 AN XY: 135736

Gnomad AFR exome AF: 0.0562

Gnomad AMR exome AF: 0.00299

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00187 AC: 2735 AN: 1461378 Hom.: 55 Cov.: 30 AF XY: 0.00165 AC XY: 1200 AN XY: 726978

Gnomad4 AFR exome AF: 0.0595

Gnomad4 AMR exome AF: 0.00372

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000282

Gnomad4 OTH exome AF: 0.00393

GnomAD4 genome AF: 0.0166 AC: 2518 AN: 152070 Hom.: 77 Cov.: 30 AF XY: 0.0169 AC XY: 1253 AN XY: 74344

Gnomad4 AFR AF: 0.0565

Gnomad4 AMR AF: 0.00766

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.0119

Alfa AF: 0.0107 Hom.: 22

Bravo AF: 0.0184

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000546

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 20, 2017	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Congenital myasthenic syndrome 18 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	12
Dann	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00049
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs79020892; hg19: chr20-10286773;