Variant 7-133356562-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021807.4(EXOC4):c.996G>C(p.Glu332Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

EXOC4
NM_021807.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.27

Variant links:

Genes affected

EXOC4 (HGNC:30389): (exocyst complex component 4) 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. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

EXOC4 links:

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ACMG classification

Classification made for transcript

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=0.08644354).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXOC4	NM_021807.4 linkuse as main transcript	c.996G>C	p.Glu332Asp	missense_variant	6/18	ENST00000253861.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXOC4	ENST00000253861.5 linkuse as main transcript	c.996G>C	p.Glu332Asp	missense_variant	6/18	1	NM_021807.4	P1	Q96A65-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

250940

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135640

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000981

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461620

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2023

The c.996G>C (p.E332D) alteration is located in exon 6 (coding exon 6) of the EXOC4 gene. This alteration results from a G to C substitution at nucleotide position 996, causing the glutamic acid (E) at amino acid position 332 to be replaced by an aspartic acid (D). 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

0.067

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.62

Cadd

Benign

Dann

Benign

0.069

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.68

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.0051

MetaRNN

Benign

0.086

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.64

N;N

MutationTaster

Benign

0.84

D;D;D

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.47

N;N

REVEL

Benign

0.082

Sift

Benign

0.89

T;T

Sift4G

Benign

0.34

T;T

Polyphen

0.0010

.;B

Vest4

0.30

MutPred

0.33

Loss of disorder (P = 0.1467);Loss of disorder (P = 0.1467);

MVP

0.63

MPC

0.12

ClinPred

0.0064

GERP RS

0.031

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.035

gMVP

0.17

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over