chr12-6464486-A-G

Variant names:

• chr12-6464486-A-G
• rs2137003108
• NM_014231.5:c.341T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014231.5(VAMP1):​c.341T>C​(p.Ile114Thr) 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. 14/24 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: VAMP1 NM_014231.5 missense, splice_region
• Scores: Splicing: ADA: 0.005114
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.23
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39993548).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014231.5. 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.341T>C	p.Ile114Thr	missense splice_region	Exon 5 of 5	NP_055046.1	P23763-1
	VAMP1	NM_199245.3		c.*390T>C		3_prime_UTR	Exon 4 of 4	NP_954740.1	P23763-3
	VAMP1	NM_001297438.2		c.340+404T>C		intron	N/A	NP_001284367.1	F5GZV7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAMP1	ENST00000396308.4	TSL:2 MANE Select	c.341T>C	p.Ile114Thr	missense splice_region	Exon 5 of 5	ENSP00000379602.3	P23763-1
	VAMP1	ENST00000361716.8	TSL:1	c.*390T>C		3_prime_UTR	Exon 4 of 4	ENSP00000355122.3	P23763-3
	VAMP1	ENST00000400911.7	TSL:1	c.340+404T>C		intron	N/A	ENSP00000383702.3	P23763-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	0.97
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.019
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		6.2
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.19
Sift	Benign	0.058	T
Polyphen		0.018	B
Vest4		0.61
MutPred		0.64		Gain of glycosylation at I114 (P = 0.0227)
MVP		0.10
MPC		0.70
ClinPred		0.74	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.080
gMVP		0.75
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0051
dbscSNV1_RF	Benign	0.074
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: rs2137003108; hg19: chr12-6573652;