1-171704528-A-G

Position:

chr1-171704528-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000236192.12(VAMP4):c.404T>C(p.Ile135Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,583,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I135V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

VAMP4
ENST00000236192.12 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.22

Variant links:

Genes affected

VAMP4 (HGNC:12645): (vesicle associated membrane protein 4) Synaptobrevins/VAMPs, syntaxins, and the 25-kD 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. This protein may play a role in trans-Golgi network-to-endosome transport. [provided by RefSeq, Jul 2008]

VAMP4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.097839266).

BS2

High AC in GnomAdExome4 at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VAMP4	NM_003762.5 linkuse as main transcript	c.404T>C	p.Ile135Thr	missense_variant	8/8	ENST00000236192.12	NP_003753.2
VAMP4	NM_001185127.2 linkuse as main transcript	c.401T>C	p.Ile134Thr	missense_variant	8/8		NP_001172056.1
VAMP4	NR_033704.2 linkuse as main transcript	n.609T>C		non_coding_transcript_exon_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VAMP4	ENST00000236192.12 linkuse as main transcript	c.404T>C	p.Ile135Thr	missense_variant	8/8	1	NM_003762.5	ENSP00000236192	P3	O75379-1
VAMP4	ENST00000367740.2 linkuse as main transcript	c.401T>C	p.Ile134Thr	missense_variant	8/8	1		ENSP00000356714	A1	O75379-2
VAMP4	ENST00000474047.5 linkuse as main transcript	c.404T>C	p.Ile135Thr	missense_variant, NMD_transcript_variant	8/9	1		ENSP00000435933		O75379-1
VAMP4	ENST00000482519.1 linkuse as main transcript	n.563T>C		non_coding_transcript_exon_variant	8/8	3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000258

AC:

AN:

232582

Hom.:

AF XY:

0.0000316

AC XY:

AN XY:

126532

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000177

Gnomad SAS exome

AF:

0.0000731

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000181

GnomAD4 exome

AF:

0.0000300

AC:

AN:

1431270

Hom.:

Cov.:

AF XY:

0.0000323

AC XY:

AN XY:

712342

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000917

Gnomad4 SAS exome

AF:

0.0000368

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000365

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152066

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000384

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2023

The c.404T>C (p.I135T) alteration is located in exon 8 (coding exon 7) of the VAMP4 gene. This alteration results from a T to C substitution at nucleotide position 404, causing the isoleucine (I) at amino acid position 135 to be replaced by a threonine (T). 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

0.11

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.020

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.68

.;T

M_CAP

Benign

0.0057

MetaRNN

Benign

0.098

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.7

M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.6

D;D

REVEL

Benign

0.084

Sift

Benign

0.078

T;T

Sift4G

Uncertain

0.0080

D;D

Polyphen

0.0

B;B

Vest4

0.11

MutPred

0.65

Loss of sheet (P = 0.0126);.;

MVP

0.068

MPC

0.21

ClinPred

0.14

GERP RS

3.5

Varity_R

0.10

gMVP

0.63

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over