chr14-57233862-T-C

Position:

chr14-57233862-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_006544.4(EXOC5):c.736A>G(p.Ile246Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,610,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

EXOC5
NM_006544.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.30

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05577284).

BS2

High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EXOC5	NM_006544.4 linkuse as main transcript	c.736A>G	p.Ile246Val	missense_variant	9/18	ENST00000621441.5	NP_006535.1
EXOC5	XM_005267272.4 linkuse as main transcript	c.850A>G	p.Ile284Val	missense_variant	9/18		XP_005267329.1
EXOC5	XM_047430882.1 linkuse as main transcript	c.571A>G	p.Ile191Val	missense_variant	9/18		XP_047286838.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
EXOC5	ENST00000621441.5 linkuse as main transcript	c.736A>G	p.Ile246Val	missense_variant	9/18	1	NM_006544.4	ENSP00000484855	P1
EXOC5	ENST00000340918.11 linkuse as main transcript	c.541A>G	p.Ile181Val	missense_variant	8/17	2		ENSP00000342100
EXOC5	ENST00000556629.1 linkuse as main transcript	n.346A>G		non_coding_transcript_exon_variant	4/6	3
EXOC5	ENST00000555148.5 linkuse as main transcript	c.*570A>G		3_prime_UTR_variant, NMD_transcript_variant	9/18	2		ENSP00000451082

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152152

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:

0.000385

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

GnomAD3 exomes

AF:

0.0000403

AC:

AN:

248428

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134762

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000501

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:

0.0000103

AC:

AN:

1458442

Hom.:

Cov.:

AF XY:

0.00000827

AC XY:

AN XY:

725708

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000303

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000331

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

Dec 19, 2022

The c.736A>G (p.I246V) alteration is located in exon 9 (coding exon 9) of the EXOC5 gene. This alteration results from a A to G substitution at nucleotide position 736, causing the isoleucine (I) at amino acid position 246 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

0.056

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.64

CADD

Benign

8.2

DANN

Benign

0.77

DEOGEN2

Benign

0.042

T;T;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.80

T;T;T

M_CAP

Benign

0.0026

MetaRNN

Benign

0.056

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.42

N;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.35

PROVEAN

Benign

0.14

.;N;N

REVEL

Benign

0.080

Sift

Benign

1.0

.;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.28

MutPred

0.56

Loss of stability (P = 0.1179);Loss of stability (P = 0.1179);.;

MVP

0.12

MPC

0.33

ClinPred

0.015

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.018

gMVP

0.11

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