14-57209665-T-C

Variant summary

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

The NM_006544.4(EXOC5):c.1840A>G(p.Ile614Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,308 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

EXOC5
NM_006544.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.02

Variant links:

Genes affected

EXOC5 (HGNC:10696): (exocyst complex component 5) 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]

EXOC5 links:

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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=0.20263398).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
EXOC5	NM_006544.4 linkuse as main transcript	c.1840A>G	p.Ile614Val	missense_variant	17/18	ENST00000621441.5
EXOC5	XM_005267272.4 linkuse as main transcript	c.1954A>G	p.Ile652Val	missense_variant	17/18
EXOC5	XM_047430882.1 linkuse as main transcript	c.1675A>G	p.Ile559Val	missense_variant	17/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
EXOC5	ENST00000621441.5 linkuse as main transcript	c.1840A>G	p.Ile614Val	missense_variant	17/18	1	NM_006544.4	P1
EXOC5	ENST00000554011.5 linkuse as main transcript	n.1559A>G		non_coding_transcript_exon_variant	7/8	1
EXOC5	ENST00000340918.11 linkuse as main transcript	c.1645A>G	p.Ile549Val	missense_variant	16/17	2
EXOC5	ENST00000555148.5 linkuse as main transcript	c.*1674A>G		3_prime_UTR_variant, NMD_transcript_variant	17/18	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248278

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134688

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000112

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460308

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726490

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000166

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

Apr 12, 2022

The c.1840A>G (p.I614V) alteration is located in exon 17 (coding exon 17) of the EXOC5 gene. This alteration results from a A to G substitution at nucleotide position 1840, causing the isoleucine (I) at amino acid position 614 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

0.081

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.39

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.058

T;T;T

Eigen

Benign

-0.18

Eigen_PC

Benign

0.041

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.0067

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.60

N;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.54

Sift4G

Benign

0.67

T;T;T

Polyphen

0.0010

B;.;B

Vest4

0.32

MutPred

0.77

Loss of catalytic residue at I614 (P = 0.0663);.;.;

MVP

0.27

MPC

0.37

ClinPred

0.11

GERP RS

5.2

Varity_R

0.068

gMVP

0.18

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