14-57222388-T-C

Variant names:

• chr14-57222388-T-C
• rs1321176716
• NM_006544.4:c.1325A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006544.4(EXOC5):​c.1325A>G​(p.Asn442Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,446,426 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EXOC5 NM_006544.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.91

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOC5	NM_006544.4	c.1325A>G	p.Asn442Ser	missense_variant	Exon 13 of 18	ENST00000621441.5	NP_006535.1
EXOC5	XM_005267272.4	c.1439A>G	p.Asn480Ser	missense_variant	Exon 13 of 18		XP_005267329.1
EXOC5	XM_047430882.1	c.1160A>G	p.Asn387Ser	missense_variant	Exon 13 of 18		XP_047286838.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOC5	ENST00000621441.5	c.1325A>G	p.Asn442Ser	missense_variant	Exon 13 of 18	1	NM_006544.4	ENSP00000484855.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1446426 Hom.: 0 Cov.: 26 AF XY: 0.00000278 AC XY: 2 AN XY: 719568

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1325A>G (p.N442S) alteration is located in exon 13 (coding exon 13) of the EXOC5 gene. This alteration results from a A to G substitution at nucleotide position 1325, causing the asparagine (N) at amino acid position 442 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	Benign	0.30
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;T;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.9	.;D;D
REVEL	Benign	0.16
Sift	Benign	0.17	.;T;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.79	P;.;P
Vest4		0.77
MutPred		0.65		Gain of disorder (P = 0.0512);Gain of disorder (P = 0.0512);.;
MVP		0.60
MPC		0.93
ClinPred		0.98	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.58

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

Other links and lift over

dbSNP: rs1321176716; hg19: chr14-57689106;