chr14-57209770-C-T

Variant names:

• chr14-57209770-C-T
• rs1445828394
• NM_006544.4:c.1735G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006544.4(EXOC5):​c.1735G>A​(p.Val579Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXOC5 NM_006544.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.76

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36365628).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOC5	NM_006544.4	c.1735G>A	p.Val579Ile	missense_variant	Exon 17 of 18	ENST00000621441.5	NP_006535.1
EXOC5	XM_005267272.4	c.1849G>A	p.Val617Ile	missense_variant	Exon 17 of 18		XP_005267329.1
EXOC5	XM_047430882.1	c.1570G>A	p.Val524Ile	missense_variant	Exon 17 of 18		XP_047286838.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOC5	ENST00000621441.5	c.1735G>A	p.Val579Ile	missense_variant	Exon 17 of 18	1	NM_006544.4	ENSP00000484855.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000414 AC: 1 AN: 241362 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130866

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000572

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1735G>A (p.V579I) alteration is located in exon 17 (coding exon 17) of the EXOC5 gene. This alteration results from a G to A substitution at nucleotide position 1735, causing the valine (V) at amino acid position 579 to be replaced by an isoleucine (I). 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	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	T;T;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	2.0	M;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.78	.;.;N
REVEL	Benign	0.12
Sift	Uncertain	0.0090	.;.;D
Sift4G	Uncertain	0.050	T;D;D
Polyphen		0.88	P;.;P
Vest4		0.43
MutPred		0.48		Gain of MoRF binding (P = 0.1405);.;.;
MVP		0.40
MPC		1.0
ClinPred		0.82	D
GERP RS		5.2
Varity_R		0.29
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1445828394; hg19: chr14-57676488;