14-57209661-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_006544.4(EXOC5):c.1844A>G(p.Tyr615Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,613,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: EXOC5 NM_006544.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.94

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 -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.779
• BS2: High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXOC5	NM_006544.4	c.1844A>G	p.Tyr615Cys	missense_variant	17/18	ENST00000621441.5
EXOC5	XM_005267272.4	c.1958A>G	p.Tyr653Cys	missense_variant	17/18
EXOC5	XM_047430882.1	c.1679A>G	p.Tyr560Cys	missense_variant	17/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXOC5	ENST00000621441.5	c.1844A>G	p.Tyr615Cys	missense_variant	17/18	1	NM_006544.4	P1
EXOC5	ENST00000554011.5	n.1563A>G		non_coding_transcript_exon_variant	7/8	1
EXOC5	ENST00000340918.11	c.1649A>G	p.Tyr550Cys	missense_variant	16/17	2
EXOC5	ENST00000555148.5	c.*1678A>G		3_prime_UTR_variant, NMD_transcript_variant	17/18	2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000242 AC: 6 AN: 248360 Hom.: 0 AF XY: 0.0000297 AC XY: 4 AN XY: 134726

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1460850 Hom.: 0 Cov.: 30 AF XY: 0.0000261 AC XY: 19 AN XY: 726734

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.00000828 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000594

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

Mar 16, 2022

The c.1844A>G (p.Y615C) alteration is located in exon 17 (coding exon 17) of the EXOC5 gene. This alteration results from a A to G substitution at nucleotide position 1844, causing the tyrosine (Y) at amino acid position 615 to be replaced by a cysteine (C). 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	0.096
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.12
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.99	D;.;D
Vest4		0.60
MutPred		0.77		Gain of helix (P = 0.0696);.;.;
MVP		0.41
MPC		1.3
ClinPred		0.89	D
GERP RS		4.0
Varity_R		0.69
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs777313493; hg19: chr14-57676379;