chr14-57229823-T-C

Variant names:

• chr14-57229823-T-C
• rs967716979
• NM_006544.4:c.1207A>G

Variant summary

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

The NM_006544.4(EXOC5):​c.1207A>G​(p.Ile403Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000654 in 1,376,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: EXOC5 NM_006544.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.22

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=0.19009307).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOC5	NM_006544.4	c.1207A>G	p.Ile403Val	missense_variant	Exon 12 of 18	ENST00000621441.5	NP_006535.1
EXOC5	XM_005267272.4	c.1321A>G	p.Ile441Val	missense_variant	Exon 12 of 18		XP_005267329.1
EXOC5	XM_047430882.1	c.1042A>G	p.Ile348Val	missense_variant	Exon 12 of 18		XP_047286838.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOC5	ENST00000621441.5	c.1207A>G	p.Ile403Val	missense_variant	Exon 12 of 18	1	NM_006544.4	ENSP00000484855.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000654 AC: 9 AN: 1376262 Hom.: 0 Cov.: 27 AF XY: 0.0000103 AC XY: 7 AN XY: 677646

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: 0.00000659

Gnomad4 OTH exome AF: 0.0000352

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1207A>G (p.I403V) alteration is located in exon 12 (coding exon 12) of the EXOC5 gene. This alteration results from a A to G substitution at nucleotide position 1207, causing the isoleucine (I) at amino acid position 403 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	0.066
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Benign	0.65
DEOGEN2	Benign	0.039	T;T;T
Eigen	Benign	-0.011
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.64	N;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.66	.;N;N
REVEL	Benign	0.17
Sift	Benign	1.0	.;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0080	B;.;B
Vest4		0.41
MutPred		0.66		Gain of disorder (P = 0.1088);Gain of disorder (P = 0.1088);.;
MVP		0.32
MPC		0.40
ClinPred		0.70	D
GERP RS		5.4
Varity_R		0.076
gMVP		0.11

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: rs967716979; hg19: chr14-57696541;