14-57229820-C-A

Variant names:

• chr14-57229820-C-A
• rs745842063
• NM_006544.4:c.1210G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006544.4(EXOC5):​c.1210G>T​(p.Asp404Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000727 in 1,376,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D404N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: EXOC5 NM_006544.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006544.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOC5	NM_006544.4	MANE Select	c.1210G>T	p.Asp404Tyr	missense	Exon 12 of 18	NP_006535.1	O00471

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOC5	ENST00000621441.5	TSL:1 MANE Select	c.1210G>T	p.Asp404Tyr	missense	Exon 12 of 18	ENSP00000484855.1	O00471
	EXOC5	ENST00000554011.5	TSL:1	n.929G>T		non_coding_transcript_exon	Exon 2 of 8
	EXOC5	ENST00000854286.1		c.1324G>T	p.Asp442Tyr	missense	Exon 12 of 18	ENSP00000524345.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.27e-7 AC: 1 AN: 1376140 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 677752

African (AFR) AF: 0.00 AC: 0 AN: 31412

American (AMR) AF: 0.00 AC: 0 AN: 35498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24602

East Asian (EAS) AF: 0.00 AC: 0 AN: 35564

South Asian (SAS) AF: 0.00 AC: 0 AN: 75240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5544

European-Non Finnish (NFE) AF: 9.41e-7 AC: 1 AN: 1062916

Other (OTH) AF: 0.00 AC: 0 AN: 56772

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	2.0	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.44		Loss of disorder (P = 0.0264)
MVP		0.76
MPC		1.3
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.77
gMVP		0.52
Mutation Taster		=13/87	disease causing

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

Other links and lift over

dbSNP: rs745842063; hg19: chr14-57696538;