14-57208791-T-C

Position:

chr14-57208791-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_006544.4(EXOC5):c.1945A>G(p.Met649Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000637 in 1,570,084 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 (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000063 ( 0 hom. )

Consequence

EXOC5
NM_006544.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.00

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10499555).

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EXOC5	NM_006544.4 linkuse as main transcript	c.1945A>G	p.Met649Val	missense_variant	18/18	ENST00000621441.5	NP_006535.1
EXOC5	XM_005267272.4 linkuse as main transcript	c.2059A>G	p.Met687Val	missense_variant	18/18		XP_005267329.1
EXOC5	XM_047430882.1 linkuse as main transcript	c.1780A>G	p.Met594Val	missense_variant	18/18		XP_047286838.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
EXOC5	ENST00000621441.5 linkuse as main transcript	c.1945A>G	p.Met649Val	missense_variant	18/18	1	NM_006544.4	ENSP00000484855	P1
EXOC5	ENST00000554011.5 linkuse as main transcript	n.1664A>G		non_coding_transcript_exon_variant	8/8	1
EXOC5	ENST00000340918.11 linkuse as main transcript	c.1750A>G	p.Met584Val	missense_variant	17/17	2		ENSP00000342100
EXOC5	ENST00000555148.5 linkuse as main transcript	c.*1779A>G		3_prime_UTR_variant, NMD_transcript_variant	18/18	2		ENSP00000451082

Frequencies

GnomAD3 genomes

AF:

0.0000724

AC:

AN:

151936

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:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000104

AC:

AN:

240214

Hom.:

AF XY:

0.0000841

AC XY:

AN XY:

130828

show subpopulations

Gnomad AFR exome

AF:

0.000132

Gnomad AMR exome

AF:

0.0000597

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000568

Gnomad SAS exome

AF:

0.000365

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000841

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000628

AC:

AN:

1418030

Hom.:

Cov.:

AF XY:

0.0000629

AC XY:

AN XY:

699950

show subpopulations

Gnomad4 AFR exome

AF:

0.000122

Gnomad4 AMR exome

AF:

0.0000457

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000300

Gnomad4 FIN exome

AF:

0.0000191

Gnomad4 NFE exome

AF:

0.0000483

Gnomad4 OTH exome

AF:

0.0000686

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152054

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000774

Hom.:

Bravo

AF:

0.0000340

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000108

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

Sep 13, 2023

The c.1945A>G (p.M649V) alteration is located in exon 18 (coding exon 18) of the EXOC5 gene. This alteration results from a A to G substitution at nucleotide position 1945, causing the methionine (M) at amino acid position 649 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

0.052

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.047

T;T;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.060

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.0072

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.14

N;.;.

MutationTaster

Benign

0.97

D;D

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.46

.;.;N

REVEL

Benign

0.057

Sift

Benign

0.11

.;.;T

Sift4G

Benign

0.12

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.15

MutPred

0.48

Loss of ubiquitination at K646 (P = 0.1179);.;.;

MVP

0.18

MPC

0.40

ClinPred

0.016

GERP RS

4.6

Varity_R

0.057

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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