14-57229820-C-T

Variant summary

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

The NM_006544.4(EXOC5):c.1210G>A(p.Asp404Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000936 in 1,528,256 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 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: EXOC5 NM_006544.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14067036).
• BS2: High AC in GnomAd at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXOC5	NM_006544.4	c.1210G>A	p.Asp404Asn	missense_variant	12/18	ENST00000621441.5
EXOC5	XM_005267272.4	c.1324G>A	p.Asp442Asn	missense_variant	12/18
EXOC5	XM_047430882.1	c.1045G>A	p.Asp349Asn	missense_variant	12/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXOC5	ENST00000621441.5	c.1210G>A	p.Asp404Asn	missense_variant	12/18	1	NM_006544.4	P1
EXOC5	ENST00000554011.5	n.929G>A		non_coding_transcript_exon_variant	2/8	1
EXOC5	ENST00000340918.11	c.1015G>A	p.Asp339Asn	missense_variant	11/17	2
EXOC5	ENST00000555148.5	c.*1044G>A		3_prime_UTR_variant, NMD_transcript_variant	12/18	2

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000272 AC: 43 AN: 158348 Hom.: 0 AF XY: 0.000264 AC XY: 22 AN XY: 83272

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000908

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000669 AC: 92 AN: 1376136 Hom.: 0 Cov.: 27 AF XY: 0.0000649 AC XY: 44 AN XY: 677750

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00158

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: 0.0000301

Gnomad4 OTH exome AF: 0.0000528

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.000511 AC XY: 38 AN XY: 74320

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00321

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.000374

ExAC AF: 0.0000536 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2022

The c.1210G>A (p.D404N) alteration is located in exon 12 (coding exon 12) of the EXOC5 gene. This alteration results from a G to A substitution at nucleotide position 1210, causing the aspartic acid (D) at amino acid position 404 to be replaced by an asparagine (N). 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	0.18
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.41
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.090	T;T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.93	D
Sift4G	Benign	0.24	T;T;T
Polyphen		1.0	D;.;D
Vest4		0.60
MutPred		0.42		Loss of phosphorylation at T405 (P = 0.1509);Loss of phosphorylation at T405 (P = 0.1509);.;
MVP		0.65
MPC		0.89
ClinPred		0.12	T
GERP RS		5.4
Varity_R		0.15
gMVP		0.21

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: rs745842063; hg19: chr14-57696538; COSMIC: COSV105238877; COSMIC: COSV105238877;