NM_020964.3:c.5583C>T

Variant names:

• chr18-45880159-G-A
• rs200372908
• NM_020964.3:c.5583C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020964.3(EPG5):​c.5583C>T​(p.Cys1861Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,611,458 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (6 hom.)
• Consequence: EPG5 NM_020964.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.583
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 18-45880159-G-A is Benign according to our data. Variant chr18-45880159-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 466255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.583 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0038 (578/152286) while in subpopulation AFR AF = 0.00864 (359/41572). AF 95% confidence interval is 0.0079. There are 3 homozygotes in GnomAd4. There are 309 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.5583C>T	p.Cys1861Cys	synonymous	Exon 32 of 44	NP_066015.2	Q9HCE0-1
	EPG5	NM_001410859.1		c.5583C>T	p.Cys1861Cys	synonymous	Exon 32 of 44	NP_001397788.1	A0A8Q3SIU6
	EPG5	NM_001410858.1		c.5583C>T	p.Cys1861Cys	synonymous	Exon 32 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.5583C>T	p.Cys1861Cys	synonymous	Exon 32 of 44	ENSP00000282041.4	Q9HCE0-1
	EPG5	ENST00000587884.2	TSL:1	n.*1323C>T		non_coding_transcript_exon	Exon 33 of 45	ENSP00000466990.2	K7ENK5
	EPG5	ENST00000590884.6	TSL:1	n.*178C>T		non_coding_transcript_exon	Exon 32 of 42	ENSP00000466403.2	K7EM87

Frequencies

GnomAD3 genomes AF: 0.00380 AC: 579 AN: 152168 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00238 AC: 581 AN: 244328 AF XY: 0.00234

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000225

Gnomad FIN exome AF: 0.00758

Gnomad NFE exome AF: 0.00148

Gnomad OTH exome AF: 0.00100

GnomAD4 exome AF: 0.00196 AC: 2853 AN: 1459172 Hom.: 6 Cov.: 31 AF XY: 0.00202 AC XY: 1469 AN XY: 725728

African (AFR) AF: 0.00820 AC: 274 AN: 33422

American (AMR) AF: 0.000605 AC: 27 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26092

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39642

South Asian (SAS) AF: 0.00315 AC: 271 AN: 86110

European-Finnish (FIN) AF: 0.00697 AC: 367 AN: 52688

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5756

European-Non Finnish (NFE) AF: 0.00162 AC: 1800 AN: 1110560

Other (OTH) AF: 0.00172 AC: 104 AN: 60296

GnomAD4 genome AF: 0.00380 AC: 578 AN: 152286 Hom.: 3 Cov.: 32 AF XY: 0.00415 AC XY: 309 AN XY: 74448

African (AFR) AF: 0.00864 AC: 359 AN: 41572

American (AMR) AF: 0.000849 AC: 13 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4824

European-Finnish (FIN) AF: 0.00941 AC: 100 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00128 AC: 87 AN: 68012

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00224 Hom.: 1

Bravo AF: 0.00350

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00186

EpiControl AF: 0.00142

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	EPG5-related disorder (1)
-	-	1	Vici syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.2
DANN	Benign	0.92
PhyloP100		-0.58
Mutation Taster		=100/0	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: rs200372908; hg19: chr18-43460124;