1-171704529-T-C

Position:

chr1-171704529-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003762.5(VAMP4):c.403A>G(p.Ile135Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. I135T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

VAMP4
NM_003762.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.31

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:

VAMP4 (HGNC:):

VAMP4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.08555624).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VAMP4	NM_003762.5 linkuse as main transcript	c.403A>G	p.Ile135Val	missense_variant	8/8	ENST00000236192.12	NP_003753.2	O75379-1Q6IAZ3
VAMP4	NM_001185127.2 linkuse as main transcript	c.400A>G	p.Ile134Val	missense_variant	8/8		NP_001172056.1	O75379-2
VAMP4	NR_033704.2 linkuse as main transcript	n.608A>G		non_coding_transcript_exon_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
VAMP4	ENST00000236192.12 linkuse as main transcript	c.403A>G	p.Ile135Val	missense_variant	8/8	1	NM_003762.5	ENSP00000236192.7	O75379-1
VAMP4	ENST00000367740.2 linkuse as main transcript	c.400A>G	p.Ile134Val	missense_variant	8/8	1		ENSP00000356714.2	O75379-2
VAMP4	ENST00000474047.5 linkuse as main transcript	n.403A>G		non_coding_transcript_exon_variant	8/9	1		ENSP00000435933.1	O75379-1
VAMP4	ENST00000482519.1 linkuse as main transcript	n.562A>G		non_coding_transcript_exon_variant	8/8	3

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1430088

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

711668

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

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

Jan 16, 2024

The c.403A>G (p.I135V) alteration is located in exon 8 (coding exon 7) of the VAMP4 gene. This alteration results from a A to G substitution at nucleotide position 403, causing the isoleucine (I) at amino acid position 135 to be replaced by a valine (V). 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

0.074

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.065

T;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.39

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.63

.;T

M_CAP

Benign

0.0052

MetaRNN

Benign

0.086

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.23

N;.

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.43

N;N

REVEL

Benign

0.035

Sift

Benign

0.43

T;T

Sift4G

Benign

0.52

T;T

Polyphen

0.0020

B;B

Vest4

0.11

MutPred

0.56

Gain of sheet (P = 0.0266);.;

MVP

0.12

MPC

0.14

ClinPred

0.091

GERP RS

2.0

Varity_R

0.024

gMVP

0.39

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