14-57209616-A-G

Variant names:

• chr14-57209616-A-G
• rs1882765199
• NM_006544.4:c.1889T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006544.4(EXOC5):​c.1889T>C​(p.Leu630Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EXOC5 NM_006544.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.15

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOC5	NM_006544.4	c.1889T>C	p.Leu630Ser	missense_variant	Exon 17 of 18	ENST00000621441.5	NP_006535.1
EXOC5	XM_005267272.4	c.2003T>C	p.Leu668Ser	missense_variant	Exon 17 of 18		XP_005267329.1
EXOC5	XM_047430882.1	c.1724T>C	p.Leu575Ser	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.1889T>C	p.Leu630Ser	missense_variant	Exon 17 of 18	1	NM_006544.4	ENSP00000484855.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461232 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726894

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1889T>C (p.L630S) alteration is located in exon 17 (coding exon 17) of the EXOC5 gene. This alteration results from a T to C substitution at nucleotide position 1889, causing the leucine (L) at amino acid position 630 to be replaced by a serine (S). 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	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.9	L;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.0	.;.;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0060	.;.;D
Sift4G	Uncertain	0.030	D;D;D
Polyphen		0.63	P;.;P
Vest4		0.94
MutPred		0.49		Loss of sheet (P = 0.0315);.;.;
MVP		0.72
MPC		1.2
ClinPred		0.97	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1882765199; hg19: chr14-57676334;