10-112464583-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_145206.4(VTI1A):​c.190C>T​(p.Pro64Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

VTI1A
NM_145206.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.93

Publications

0 publications found
Variant links:
Genes affected
VTI1A (HGNC:17792): (vesicle transport through interaction with t-SNAREs 1A) The protein encoded by this gene is a member of the family of soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptors (SNAREs) that function in intracellular trafficking. This family member is involved in vesicular transport between endosomes and the trans-Golgi network. It is a vesicle-associated SNARE (v-SNARE) that interacts with target membrane SNAREs (t-SNAREs). Polymorphisms in this gene have been associated with binocular function, and also with susceptibility to colorectal and lung cancers. A recurrent rearrangement has been found between this gene and the transcription factor 7-like 2 (TCF7L2) gene in colorectal cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.18375137).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VTI1ANM_145206.4 linkc.190C>T p.Pro64Ser missense_variant Exon 3 of 8 ENST00000393077.3 NP_660207.2 Q96AJ9-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VTI1AENST00000393077.3 linkc.190C>T p.Pro64Ser missense_variant Exon 3 of 8 2 NM_145206.4 ENSP00000376792.2 Q96AJ9-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152170
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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
AF:
0.00000137
AC:
2
AN:
1460694
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726632
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33408
American (AMR)
AF:
0.00
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39590
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86170
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53358
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
9.00e-7
AC:
1
AN:
1111218
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60328
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152170
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74332
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
41424
American (AMR)
AF:
0.0000654
AC:
1
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10612
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68042
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.0000468
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 03, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.190C>T (p.P64S) alteration is located in exon 3 (coding exon 3) of the VTI1A gene. This alteration results from a C to T substitution at nucleotide position 190, causing the proline (P) at amino acid position 64 to be replaced by a serine (S). 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
0.077
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
22
DANN
Benign
0.92
DEOGEN2
Benign
0.12
.;T
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.0070
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Benign
0.0027
T
MetaRNN
Benign
0.18
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.90
L;L
PhyloP100
2.9
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-0.92
N;N
REVEL
Benign
0.13
Sift
Benign
0.75
T;T
Sift4G
Benign
1.0
T;T
Polyphen
0.0030
.;B
Vest4
0.36
MutPred
0.39
Loss of catalytic residue at P64 (P = 0.0109);Loss of catalytic residue at P64 (P = 0.0109);
MVP
0.37
MPC
0.17
ClinPred
0.57
D
GERP RS
5.6
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.7
Varity_R
0.085
gMVP
0.27
Mutation Taster
=66/34
polymorphism

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

Other links and lift over

dbSNP: rs1169292996; hg19: chr10-114224342; API