rs368086133

Variant names:

• chr18-45899422-G-A
• rs368086133
• NM_020964.3:c.4791C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_020964.3(EPG5):​c.4791C>T​(p.Ala1597Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000502 in 1,614,074 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (0 hom.)
• Consequence: EPG5 NM_020964.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.236
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 18-45899422-G-A is Benign according to our data. Variant chr18-45899422-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 466252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.236 with no splicing effect.

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.4791C>T	p.Ala1597Ala	synonymous	Exon 27 of 44	NP_066015.2	Q9HCE0-1
	EPG5	NM_001410859.1		c.4791C>T	p.Ala1597Ala	synonymous	Exon 27 of 44	NP_001397788.1	A0A8Q3SIU6
	EPG5	NM_001410858.1		c.4791C>T	p.Ala1597Ala	synonymous	Exon 27 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.4791C>T	p.Ala1597Ala	synonymous	Exon 27 of 44	ENSP00000282041.4	Q9HCE0-1
	EPG5	ENST00000587884.2	TSL:1	n.*531C>T		non_coding_transcript_exon	Exon 28 of 45	ENSP00000466990.2	K7ENK5
	EPG5	ENST00000590884.6	TSL:1	n.4791C>T		non_coding_transcript_exon	Exon 27 of 42	ENSP00000466403.2	K7EM87

Frequencies

GnomAD3 genomes AF: 0.000395 AC: 60 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000232 AC: 58 AN: 249536 AF XY: 0.000266

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000388

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000514 AC: 751 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.000509 AC XY: 370 AN XY: 727244

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000492 AC: 22 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000629 AC: 700 AN: 1112006

Other (OTH) AF: 0.000364 AC: 22 AN: 60394

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74412

African (AFR) AF: 0.000217 AC: 9 AN: 41492

American (AMR) AF: 0.000327 AC: 5 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000350 Hom.: 0

Bravo AF: 0.000370

EpiCase AF: 0.000436

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.59
DANN	Benign	0.46
PhyloP100		-0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs368086133; hg19: chr18-43479387; COSMIC: COSV56349454;