chr18-45880151-C-T

Variant names:

• chr18-45880151-C-T
• rs34064739
• NM_020964.3:c.5591G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020964.3(EPG5):​c.5591G>A​(p.Ser1864Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00914 in 1,611,596 control chromosomes in the GnomAD database, including 1,157 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1864R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.049 (605 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (552 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.279
• Publications: 5 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012777448).
• BP6: Variant 18-45880151-C-T is Benign according to our data. Variant chr18-45880151-C-T is described in ClinVar as Benign. ClinVar VariationId is 466257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

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.5591G>A	p.Ser1864Asn	missense	Exon 32 of 44	NP_066015.2
	EPG5	NM_001410859.1		c.5591G>A	p.Ser1864Asn	missense	Exon 32 of 44	NP_001397788.1
	EPG5	NM_001410858.1		c.5591G>A	p.Ser1864Asn	missense	Exon 32 of 44	NP_001397787.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPG5	ENST00000282041.11	TSL:1 MANE Select	c.5591G>A	p.Ser1864Asn	missense	Exon 32 of 44	ENSP00000282041.4
	EPG5	ENST00000587884.2	TSL:1	n.*1331G>A		non_coding_transcript_exon	Exon 33 of 45	ENSP00000466990.2
	EPG5	ENST00000590884.6	TSL:1	n.*186G>A		non_coding_transcript_exon	Exon 32 of 42	ENSP00000466403.2

Frequencies

GnomAD3 genomes AF: 0.0488 AC: 7430 AN: 152108 Hom.: 602 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.0296

GnomAD2 exomes AF: 0.0125 AC: 3072 AN: 244996 AF XY: 0.00930

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.00865

Gnomad ASJ exome AF: 0.00623

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000419

Gnomad OTH exome AF: 0.00551

GnomAD4 exome AF: 0.00500 AC: 7296 AN: 1459370 Hom.: 552 Cov.: 31 AF XY: 0.00429 AC XY: 3115 AN XY: 725820

African (AFR) AF: 0.170 AC: 5687 AN: 33408

American (AMR) AF: 0.00984 AC: 439 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00563 AC: 147 AN: 26100

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

South Asian (SAS) AF: 0.000163 AC: 14 AN: 86118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52794

Middle Eastern (MID) AF: 0.00469 AC: 27 AN: 5754

European-Non Finnish (NFE) AF: 0.000256 AC: 284 AN: 1110646

Other (OTH) AF: 0.0116 AC: 698 AN: 60288

GnomAD4 genome AF: 0.0489 AC: 7442 AN: 152226 Hom.: 605 Cov.: 32 AF XY: 0.0477 AC XY: 3547 AN XY: 74418

African (AFR) AF: 0.169 AC: 7009 AN: 41514

American (AMR) AF: 0.0195 AC: 299 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68016

Other (OTH) AF: 0.0293 AC: 62 AN: 2114

Alfa AF: 0.00927 Hom.: 141

Bravo AF: 0.0559

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.154 AC: 578

ESP6500EA AF: 0.00159 AC: 13

ExAC AF: 0.0149 AC: 1800

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.00113

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Vici syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.9
DANN	Benign	0.90
DEOGEN2	Benign	0.0045	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0041	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.76	N
PhyloP100		0.28
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.064
Sift	Benign	0.61	T
Sift4G	Benign	0.067	T
Polyphen		0.0010	B
Vest4		0.046
MPC		0.15
ClinPred		0.0013	T
GERP RS		-2.5
Varity_R		0.046
gMVP		0.14
Mutation Taster		=97/3	polymorphism (auto)

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: rs34064739; hg19: chr18-43460116;