14-57208791-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.00

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10499555).
• BS2: High AC in GnomAd at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXOC5	NM_006544.4	c.1945A>G	p.Met649Val	missense_variant	18/18	ENST00000621441.5
EXOC5	XM_005267272.4	c.2059A>G	p.Met687Val	missense_variant	18/18
EXOC5	XM_047430882.1	c.1780A>G	p.Met594Val	missense_variant	18/18

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000724 AC: 11 AN: 151936 Hom.: 0 Cov.: 32

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: 25 AN: 240214 Hom.: 0 AF XY: 0.0000841 AC XY: 11 AN XY: 130828

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: 89 AN: 1418030 Hom.: 0 Cov.: 26 AF XY: 0.0000629 AC XY: 44 AN XY: 699950

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: 11 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74342

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.: 0

Bravo AF: 0.0000340

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000108 AC: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	18
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	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	N;.;.
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.40	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	T
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

Other links and lift over

dbSNP: rs780117264; hg19: chr14-57675509;