12-6464510-C-T

Variant names:

• chr12-6464510-C-T
• rs1592145926
• ENST00000361716.8:c.*366G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_199245.3(VAMP1):​c.*366G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: VAMP1 NM_199245.3 3_prime_UTR
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.628
• Publications: 0 publications found

Genes affected

VAMP1 (HGNC:12642): (vesicle associated membrane protein 1) Synapotobrevins, syntaxins, and the synaptosomal-associated protein SNAP25 are the main components of a protein complex involved in the docking and/or fusion of synaptic vesicles with the presynaptic membrane. The protein encoded by this gene is a member of the vesicle-associated membrane protein (VAMP)/synaptobrevin family. Mutations in this gene are associated with autosomal dominant spastic ataxia 1. Multiple alternative splice variants have been described, but the full-length nature of some variants has not been defined. [provided by RefSeq, Jul 2014]

TAPBPL (HGNC:30683): (TAP binding protein like) Tapasin, or TAPBP (MIM 601962), is a member of the variable-constant Ig superfamily that links major histocompatibility complex (MHC) class I molecules to the transporter associated with antigen processing (TAP; see MIM 170260) in the endoplasmic reticulum (ER). The TAPBP gene is located near the MHC complex on chromosome 6p21.3. TAPBPL is a member of the Ig superfamily that is localized on chromosome 12p13.3, a region somewhat paralogous to the MHC.[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 12-6464510-C-T is Pathogenic according to our data. Variant chr12-6464510-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3256752.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199245.3. 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
	VAMP1	NM_014231.5	MANE Select	c.341-24G>A		intron	N/A	NP_055046.1	P23763-1
	VAMP1	NM_199245.3		c.*366G>A		3_prime_UTR	Exon 4 of 4	NP_954740.1	P23763-3
	VAMP1	NM_001297438.2		c.340+380G>A		intron	N/A	NP_001284367.1	F5GZV7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAMP1	ENST00000361716.8	TSL:1	c.*366G>A		3_prime_UTR	Exon 4 of 4	ENSP00000355122.3	P23763-3
	VAMP1	ENST00000396308.4	TSL:2 MANE Select	c.341-24G>A		intron	N/A	ENSP00000379602.3	P23763-1
	VAMP1	ENST00000400911.7	TSL:1	c.340+380G>A		intron	N/A	ENSP00000383702.3	P23763-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1335968 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 652910

African (AFR) AF: 0.00 AC: 0 AN: 29070

American (AMR) AF: 0.00 AC: 0 AN: 24320

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20468

East Asian (EAS) AF: 0.00 AC: 0 AN: 35490

South Asian (SAS) AF: 0.00 AC: 0 AN: 67304

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5348

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1051608

Other (OTH) AF: 0.00 AC: 0 AN: 55234

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Myasthenic syndrome, congenital, 25, presynaptic (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Benign	0.90
PhyloP100		0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: -2
DS_AL_spliceai		0.62		Position offset: -24

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

Other links and lift over

dbSNP: rs1592145926; hg19: chr12-6573676;