chr18-45876304-G-C

Variant names:

• chr18-45876304-G-C
• rs777008903
• NM_020964.3:c.5981C>G

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.5981C>G​(p.Thr1994Ser) 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. 15/22 in silico tools predict a benign 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. T1994I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.25
• 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: 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=0.10468972).

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.5981C>G	p.Thr1994Ser	missense	Exon 35 of 44	NP_066015.2	Q9HCE0-1
	EPG5	NM_001410859.1		c.5978C>G	p.Thr1993Ser	missense	Exon 35 of 44	NP_001397788.1	A0A8Q3SIU6
	EPG5	NM_001410858.1		c.5981C>G	p.Thr1994Ser	missense	Exon 35 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.5981C>G	p.Thr1994Ser	missense	Exon 35 of 44	ENSP00000282041.4	Q9HCE0-1
	EPG5	ENST00000587884.2	TSL:1	n.*1721C>G		non_coding_transcript_exon	Exon 36 of 45	ENSP00000466990.2	K7ENK5
	EPG5	ENST00000587884.2	TSL:1	n.*1721C>G		3_prime_UTR	Exon 36 of 45	ENSP00000466990.2	K7ENK5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.0064	T
Eigen	Benign	0.048
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.078
Sift	Benign	0.42	T
Sift4G	Benign	0.070	T
Polyphen		0.015	B
Vest4		0.20
MutPred		0.20		Gain of disorder (P = 0.0489)
MVP		0.35
MPC		0.14
ClinPred		0.46	T
GERP RS		5.9
Varity_R		0.082
gMVP		0.062

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: rs777008903; hg19: chr18-43456269;