18-45865765-CAAAAAAA-CAAAAAAAA

Variant names:

• chr18-45865765-C-CA
• rs11333207
• NM_020964.3:c.6622-7dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_020964.3(EPG5):​c.6622-7dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0854 in 1,378,268 control chromosomes in the GnomAD database, including 258 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (227 hom., cov: 25)
  • Exomes 𝑓: 0.086 (31 hom.)
• Consequence: EPG5 NM_020964.3 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.327
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 18-45865765-C-CA is Benign according to our data. Variant chr18-45865765-C-CA is described in ClinVar as Benign. ClinVar VariationId is 769442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.108 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.6622-7dupT		splice_region intron	N/A	NP_066015.2	Q9HCE0-1
	EPG5	NM_001410859.1		c.6619-7dupT		splice_region intron	N/A	NP_001397788.1	A0A8Q3SIU6
	EPG5	NM_001410858.1		c.6622-7dupT		splice_region intron	N/A	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.6622-7_6622-6insT		splice_region intron	N/A	ENSP00000282041.4	Q9HCE0-1
	EPG5	ENST00000587884.2	TSL:1	n.*2362-7_*2362-6insT		splice_region intron	N/A	ENSP00000466990.2	K7ENK5
	EPG5	ENST00000590884.6	TSL:1	n.*934-7_*934-6insT		splice_region intron	N/A	ENSP00000466403.2	K7EM87

Frequencies

GnomAD3 genomes AF: 0.0748 AC: 7663 AN: 102444 Hom.: 227 Cov.: 25

Gnomad AFR AF: 0.0276

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.0564

Gnomad ASJ AF: 0.0645

Gnomad EAS AF: 0.00752

Gnomad SAS AF: 0.0253

Gnomad FIN AF: 0.0907

Gnomad MID AF: 0.105

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.0962

GnomAD2 exomes AF: 0.0715 AC: 7496 AN: 104766 AF XY: 0.0741

Gnomad AFR exome AF: 0.0824

Gnomad AMR exome AF: 0.0446

Gnomad ASJ exome AF: 0.0516

Gnomad EAS exome AF: 0.0591

Gnomad FIN exome AF: 0.0620

Gnomad NFE exome AF: 0.0862

Gnomad OTH exome AF: 0.0729

GnomAD4 exome AF: 0.0863 AC: 110101 AN: 1275814 Hom.: 31 Cov.: 0 AF XY: 0.0841 AC XY: 53074 AN XY: 630982

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0507 AC: 1405 AN: 27706

American (AMR) AF: 0.0364 AC: 1109 AN: 30426

Ashkenazi Jewish (ASJ) AF: 0.0544 AC: 1099 AN: 20196

East Asian (EAS) AF: 0.0227 AC: 843 AN: 37154

South Asian (SAS) AF: 0.0437 AC: 2897 AN: 66320

European-Finnish (FIN) AF: 0.0622 AC: 2291 AN: 36828

Middle Eastern (MID) AF: 0.0614 AC: 254 AN: 4140

European-Non Finnish (NFE) AF: 0.0961 AC: 96095 AN: 999880

Other (OTH) AF: 0.0773 AC: 4108 AN: 53164

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0748 AC: 7665 AN: 102454 Hom.: 227 Cov.: 25 AF XY: 0.0719 AC XY: 3541 AN XY: 49226

African (AFR) AF: 0.0277 AC: 698 AN: 25178

American (AMR) AF: 0.0564 AC: 641 AN: 11370

Ashkenazi Jewish (ASJ) AF: 0.0645 AC: 154 AN: 2386

East Asian (EAS) AF: 0.00755 AC: 30 AN: 3974

South Asian (SAS) AF: 0.0254 AC: 92 AN: 3626

European-Finnish (FIN) AF: 0.0907 AC: 566 AN: 6242

Middle Eastern (MID) AF: 0.112 AC: 17 AN: 152

European-Non Finnish (NFE) AF: 0.110 AC: 5231 AN: 47502

Other (OTH) AF: 0.0951 AC: 137 AN: 1440

Alfa AF: 0.0215 Hom.: 20

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)
-	-	1	Vici syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.33
Mutation Taster		=100/0	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: rs11333207; hg19: chr18-43445730; COSMIC: COSV56347554;