5-447678-A-G

Variant names:

• chr5-447678-A-G
• rs1324962726
• NM_007277.5:c.290A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007277.5(EXOC3):​c.290A>G​(p.Lys97Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000278 in 1,438,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: EXOC3 NM_007277.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.04

Genes affected

EXOC3 (HGNC:30378): (exocyst complex component 3) 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.098368764).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOC3	NM_007277.5	c.290A>G	p.Lys97Arg	missense_variant	Exon 3 of 13	ENST00000512944.6	NP_009208.2
EXOC3	XM_047416683.1	c.290A>G	p.Lys97Arg	missense_variant	Exon 3 of 7		XP_047272639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOC3	ENST00000512944.6	c.290A>G	p.Lys97Arg	missense_variant	Exon 3 of 13	1	NM_007277.5	ENSP00000425587.1
EXOC3	ENST00000315013.9	c.290A>G	p.Lys97Arg	missense_variant	Exon 2 of 12	2		ENSP00000323377.5
EXOC3	ENST00000515601.6	n.290A>G		non_coding_transcript_exon_variant	Exon 3 of 12	5		ENSP00000424404.1
EXOC3	ENST00000508022.1	c.*84A>G		downstream_gene_variant		5		ENSP00000422596.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000278 AC: 4 AN: 1438362 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 713178

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: 0.00000363

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.290A>G (p.K97R) alteration is located in exon 3 (coding exon 2) of the EXOC3 gene. This alteration results from a A to G substitution at nucleotide position 290, causing the lysine (K) at amino acid position 97 to be replaced by an arginine (R). 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	0.086
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.1
DANN	Benign	0.88
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.76	.;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.098	T;T
MetaSVM	Benign	-0.95	T
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.44	N;N
REVEL	Benign	0.12
Sift	Benign	0.14	T;T
Sift4G	Benign	0.30	T;T
Vest4		0.13
MVP		0.15
MPC		0.40
ClinPred		0.027	T
GERP RS		-6.4
gMVP		0.16

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: rs1324962726; hg19: chr5-447793;