18-45860321-C-T

Variant names:

• chr18-45860321-C-T
• rs547681142
• NM_020964.3:c.6792G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020964.3(EPG5):​c.6792G>A​(p.Met2264Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M2264T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23745415).

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.6792G>A	p.Met2264Ile	missense	Exon 40 of 44	NP_066015.2	Q9HCE0-1
	EPG5	NM_001410859.1		c.6789G>A	p.Met2263Ile	missense	Exon 40 of 44	NP_001397788.1	A0A8Q3SIU6
	EPG5	NM_001410858.1		c.6792G>A	p.Met2264Ile	missense	Exon 40 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.6792G>A	p.Met2264Ile	missense	Exon 40 of 44	ENSP00000282041.4	Q9HCE0-1
	EPG5	ENST00000587884.2	TSL:1	n.*2532G>A		non_coding_transcript_exon	Exon 41 of 45	ENSP00000466990.2	K7ENK5
	EPG5	ENST00000590884.6	TSL:1	n.*1104G>A		non_coding_transcript_exon	Exon 38 of 42	ENSP00000466403.2	K7EM87

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.050	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.066
Sift	Benign	0.29	T
Sift4G	Uncertain	0.037	D
Polyphen		0.40	B
Vest4		0.61
MutPred		0.33		Loss of disorder (P = 0.0675)
MVP		0.40
MPC		0.42
ClinPred		0.82	D
GERP RS		5.6
Varity_R		0.23
gMVP		0.30
Mutation Taster		=70/30	polymorphism

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: rs547681142; hg19: chr18-43440286;