5-447725-G-A

Variant names:

• chr5-447725-G-A
• rs372946771
• NM_007277.5:c.337G>A

Variant summary

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

The NM_007277.5(EXOC3):​c.337G>A​(p.Val113Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,576,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: EXOC3 NM_007277.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.56

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=0.17376691).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOC3	NM_007277.5	c.337G>A	p.Val113Met	missense_variant	Exon 3 of 13	ENST00000512944.6	NP_009208.2
EXOC3	XM_047416683.1	c.337G>A	p.Val113Met	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.337G>A	p.Val113Met	missense_variant	Exon 3 of 13	1	NM_007277.5	ENSP00000425587.1
EXOC3	ENST00000315013.9	c.337G>A	p.Val113Met	missense_variant	Exon 2 of 12	2		ENSP00000323377.5
EXOC3	ENST00000515601.6	n.337G>A		non_coding_transcript_exon_variant	Exon 3 of 12	5		ENSP00000424404.1
EXOC3	ENST00000508022.1	c.*131G>A		downstream_gene_variant		5		ENSP00000422596.1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000240 AC: 47 AN: 196204 Hom.: 0 AF XY: 0.000247 AC XY: 26 AN XY: 105346

Gnomad AFR exome AF: 0.0000878

Gnomad AMR exome AF: 0.000596

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000108

Gnomad NFE exome AF: 0.000307

Gnomad OTH exome AF: 0.000197

GnomAD4 exome AF: 0.000122 AC: 174 AN: 1424092 Hom.: 0 Cov.: 31 AF XY: 0.000139 AC XY: 98 AN XY: 704096

Gnomad4 AFR exome AF: 0.0000919

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.0000586

Gnomad4 NFE exome AF: 0.000132

Gnomad4 OTH exome AF: 0.000119

GnomAD4 genome AF: 0.000329 AC: 50 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.000417 AC XY: 31 AN XY: 74344

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000193 Hom.: 0

Bravo AF: 0.000370

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.000149 AC: 18

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.337G>A (p.V113M) alteration is located in exon 3 (coding exon 2) of the EXOC3 gene. This alteration results from a G to A substitution at nucleotide position 337, causing the valine (V) at amino acid position 113 to be replaced by a methionine (M). 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	Uncertain	0.36
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	-0.0061
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.87	T
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	0.22	N;N
REVEL	Benign	0.28
Sift	Benign	0.37	T;T
Sift4G	Benign	0.20	T;T
Vest4		0.79
MVP		0.14
MPC		1.4
ClinPred		0.094	T
GERP RS		5.4
gMVP		0.52

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: rs372946771; hg19: chr5-447840; COSMIC: COSV59267001; COSMIC: COSV59267001;