chr18-45878380-C-A

Variant names:

• chr18-45878380-C-A
• rs763614919
• NM_020964.3:c.5938G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_020964.3(EPG5):​c.5938G>T​(p.Glu1980*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. E1980E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EPG5 NM_020964.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.03
• Publications: 1 publications found

Genes affected

EPG5 (HGNC:29331): (ectopic P-granules 5 autophagy tethering factor) This gene encodes a large coiled coil domain-containing protein that functions in autophagy during starvation conditions. Mutations in this gene cause Vici syndrome. [provided by RefSeq, Aug 2015]

EPG5 Gene-Disease associations (from GenCC):

• Vici syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-45878380-C-A is Pathogenic according to our data. Variant chr18-45878380-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 581925.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020964.3. 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
	EPG5	NM_020964.3	MANE Select	c.5938G>T	p.Glu1980*	stop_gained	Exon 34 of 44	NP_066015.2	Q9HCE0-1
	EPG5	NM_001410859.1		c.5938G>T	p.Glu1980*	stop_gained	Exon 34 of 44	NP_001397788.1	A0A8Q3SIU6
	EPG5	NM_001410858.1		c.5938G>T	p.Glu1980*	stop_gained	Exon 34 of 44	NP_001397787.1	A0A8Q3SIJ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPG5	ENST00000282041.11	TSL:1 MANE Select	c.5938G>T	p.Glu1980*	stop_gained	Exon 34 of 44	ENSP00000282041.4	Q9HCE0-1
	EPG5	ENST00000587884.2	TSL:1	n.*1678G>T		non_coding_transcript_exon	Exon 35 of 45	ENSP00000466990.2	K7ENK5
	EPG5	ENST00000590884.6	TSL:1	n.*533G>T		non_coding_transcript_exon	Exon 34 of 42	ENSP00000466403.2	K7EM87

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Vici syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	41
DANN	Uncertain	0.99
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.84	D
PhyloP100		2.0
Vest4		0.12
GERP RS		5.0
Mutation Taster		=6/194	disease causing (ClinVar)

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: rs763614919; hg19: chr18-43458345;