rs730882233

Variant names:

• chr7-133817543-A-G
• rs730882233
• NM_021807.4:c.1733A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3 PP5

The ENST00000253861.5(EXOC4):​c.1733A>G​(p.Gln578Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000687 in 1,455,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: EXOC4 ENST00000253861.5 missense, splice_region
• Scores: Splicing: ADA: 0.9977
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.95
• Publications: 4 publications found

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]

LOC101928861 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 7-133817543-A-G is Pathogenic according to our data. Variant chr7-133817543-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 183330.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000253861.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOC4	NM_021807.4	MANE Select	c.1733A>G	p.Gln578Arg	missense splice_region	Exon 11 of 18	NP_068579.3
	LOC101928861	NR_120513.1		n.821+4615T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOC4	ENST00000253861.5	TSL:1 MANE Select	c.1733A>G	p.Gln578Arg	missense splice_region	Exon 11 of 18	ENSP00000253861.4
	EXOC4	ENST00000850617.1		c.1733A>G	p.Gln578Arg	missense splice_region	Exon 11 of 20	ENSP00000520904.1
	EXOC4	ENST00000460346.5	TSL:4	n.489A>G		splice_region non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000687 AC: 10 AN: 1455460 Hom.: 0 Cov.: 28 AF XY: 0.00000690 AC XY: 5 AN XY: 724542

African (AFR) AF: 0.00 AC: 0 AN: 33370

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5748

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106340

Other (OTH) AF: 0.0000499 AC: 3 AN: 60164

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Meckel-Gruber syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.97	L
PhyloP100		8.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.22
Sift	Benign	0.057	T
Sift4G	Uncertain	0.048	D
Polyphen		0.98	D
Vest4		0.91
MutPred		0.35		Gain of MoRF binding (P = 0.0859)
MVP		0.82
MPC		0.53
ClinPred		0.89	D
GERP RS		4.7
Varity_R		0.14
gMVP		0.74
Mutation Taster		=29/71	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.040		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: rs730882233; hg19: chr7-133502296;