5-446269-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_007277.5(EXOC3):​c.64C>T​(p.Arg22Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000223 in 1,613,836 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

EXOC3
NM_007277.5 missense

Scores

4
7
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.02
Variant links:
Genes affected
EXOC3 (HGNC:30378): (exocyst complex component 3) The protein encoded by this gene is a component of the exocyst complex, a multiple protein complex essential for targeting exocytic vesicles to specific docking sites on the plasma membrane. Though best characterized in yeast, the component proteins and functions of exocyst complex have been demonstrated to be highly conserved in higher eukaryotes. At least eight components of the exocyst complex, including this protein, are found to interact with the actin cytoskeletal remodeling and vesicle transport machinery. The complex is also essential for the biogenesis of epithelial cell surface polarity. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.013579756).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EXOC3NM_007277.5 linkc.64C>T p.Arg22Cys missense_variant Exon 2 of 13 ENST00000512944.6 NP_009208.2 O60645A0A024QYZ6Q69YP2
EXOC3XM_047416683.1 linkc.64C>T p.Arg22Cys missense_variant Exon 2 of 7 XP_047272639.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EXOC3ENST00000512944.6 linkc.64C>T p.Arg22Cys missense_variant Exon 2 of 13 1 NM_007277.5 ENSP00000425587.1 O60645

Frequencies

GnomAD3 genomes
AF:
0.000184
AC:
28
AN:
152200
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000589
Gnomad ASJ
AF:
0.00461
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.000454
AC:
113
AN:
249138
Hom.:
0
AF XY:
0.000437
AC XY:
59
AN XY:
135156
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000203
Gnomad ASJ exome
AF:
0.00826
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000151
Gnomad OTH exome
AF:
0.000993
GnomAD4 exome
AF:
0.000227
AC:
332
AN:
1461636
Hom.:
1
Cov.:
31
AF XY:
0.000250
AC XY:
182
AN XY:
727100
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000246
Gnomad4 ASJ exome
AF:
0.00846
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000477
Gnomad4 OTH exome
AF:
0.000762
GnomAD4 genome
AF:
0.000184
AC:
28
AN:
152200
Hom.:
0
Cov.:
33
AF XY:
0.000215
AC XY:
16
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000589
Gnomad4 ASJ
AF:
0.00461
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000956
Alfa
AF:
0.000604
Hom.:
0
Bravo
AF:
0.000230
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000480
AC:
4
ExAC
AF:
0.000240
AC:
29
EpiCase
AF:
0.00
EpiControl
AF:
0.000178

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jul 06, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.64C>T (p.R22C) alteration is located in exon 2 (coding exon 1) of the EXOC3 gene. This alteration results from a C to T substitution at nucleotide position 64, causing the arginine (R) at amino acid position 22 to be replaced by a cysteine (C). 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
Pathogenic
0.94
BayesDel_addAF
Benign
-0.067
T
BayesDel_noAF
Uncertain
-0.050
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.37
.;T;.
Eigen
Uncertain
0.20
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.95
.;D;D
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.014
T;T;T
MetaSVM
Benign
-1.1
T
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-6.0
D;D;D
REVEL
Benign
0.20
Sift
Pathogenic
0.0
D;D;D
Sift4G
Uncertain
0.0030
D;D;D
Vest4
0.90
MVP
0.42
MPC
1.6
ClinPred
0.19
T
GERP RS
4.3
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.8
gMVP
0.62

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.

Other links and lift over

dbSNP: rs201561285; hg19: chr5-446384; API