rs201678945

Variant names:

• chr18-45925838-G-A
• rs201678945
• NM_020964.3:c.2618C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-45925838-G-A
• chr18-45925838-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_020964.3(EPG5):​c.2618C>T​(p.Ala873Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,580,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A873A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.44
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17295471).

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.2618C>T	p.Ala873Val	missense	Exon 14 of 44	NP_066015.2	Q9HCE0-1
	EPG5	NM_001410859.1		c.2618C>T	p.Ala873Val	missense	Exon 14 of 44	NP_001397788.1	A0A8Q3SIU6
	EPG5	NM_001410858.1		c.2618C>T	p.Ala873Val	missense	Exon 14 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.2618C>T	p.Ala873Val	missense	Exon 14 of 44	ENSP00000282041.4	Q9HCE0-1
	EPG5	ENST00000587884.2	TSL:1	n.2618C>T		non_coding_transcript_exon	Exon 14 of 45	ENSP00000466990.2	K7ENK5
	EPG5	ENST00000587974.1	TSL:1	n.2653C>T		non_coding_transcript_exon	Exon 14 of 24

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000745 AC: 17 AN: 228326 AF XY: 0.0000641

Gnomad AFR exome AF: 0.0000691

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000632

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000112

Gnomad OTH exome AF: 0.000186

GnomAD4 exome AF: 0.000113 AC: 162 AN: 1428018 Hom.: 0 Cov.: 30 AF XY: 0.000100 AC XY: 71 AN XY: 709534

African (AFR) AF: 0.0000622 AC: 2 AN: 32152

American (AMR) AF: 0.0000262 AC: 1 AN: 38106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25336

East Asian (EAS) AF: 0.000184 AC: 7 AN: 37950

South Asian (SAS) AF: 0.0000376 AC: 3 AN: 79808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52716

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.000133 AC: 146 AN: 1097234

Other (OTH) AF: 0.0000508 AC: 3 AN: 59024

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74412

African (AFR) AF: 0.0000482 AC: 2 AN: 41516

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.0000943 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.0000662 AC: 8

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.083
Sift	Benign	0.22	T
Sift4G	Uncertain	0.030	D
Polyphen		0.95	P
Vest4		0.30
MVP		0.40
MPC		0.62
ClinPred		0.17	T
GERP RS		5.5
Varity_R		0.032
gMVP		0.21
Mutation Taster		=88/12	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: rs201678945; hg19: chr18-43505804; COSMIC: COSV56356280;