18-45865765-CAAAAAAA-CAAAAAAAAAAAAAAAAAA

Variant names:

• chr18-45865765-C-CAAAAAAAAAAA
• rs11333207
• NM_020964.3:c.6622-17_6622-7dupTTTTTTTTTTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_020964.3(EPG5):​c.6622-17_6622-7dupTTTTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000651 in 1,410,880 control chromosomes in the GnomAD database, including 4 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (4 hom., cov: 25)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: EPG5 NM_020964.3 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 18-45865765-C-CAAAAAAAAAAA is Benign according to our data. Variant chr18-45865765-C-CAAAAAAAAAAA is described in ClinVar as Likely_benign. ClinVar VariationId is 1107893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00692 (709/102384) while in subpopulation AFR AF = 0.0209 (525/25068). AF 95% confidence interval is 0.0195. There are 4 homozygotes in GnomAd4. There are 340 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPG5	NM_020964.3	c.6622-17_6622-7dupTTTTTTTTTTT		splice_region_variant, intron_variant	Intron 38 of 43	ENST00000282041.11	NP_066015.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPG5	ENST00000282041.11	c.6622-7_6622-6insTTTTTTTTTTT		splice_region_variant, intron_variant	Intron 38 of 43	1	NM_020964.3	ENSP00000282041.4

Frequencies

GnomAD3 genomes AF: 0.00691 AC: 707 AN: 102376 Hom.: 4 Cov.: 25

Gnomad AFR AF: 0.0209

Gnomad AMI AF: 0.00169

Gnomad AMR AF: 0.00671

Gnomad ASJ AF: 0.00210

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000549

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.00177

Gnomad OTH AF: 0.0105

GnomAD4 exome AF: 0.000160 AC: 210 AN: 1308496 Hom.: 0 Cov.: 0 AF XY: 0.000158 AC XY: 102 AN XY: 647134

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

African (AFR) AF: 0.00234 AC: 66 AN: 28158

American (AMR) AF: 0.000423 AC: 13 AN: 30766

Ashkenazi Jewish (ASJ) AF: 0.000339 AC: 7 AN: 20622

East Asian (EAS) AF: 0.00 AC: 0 AN: 37546

South Asian (SAS) AF: 0.0000734 AC: 5 AN: 68124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37564

Middle Eastern (MID) AF: 0.00118 AC: 5 AN: 4222

European-Non Finnish (NFE) AF: 0.0000915 AC: 94 AN: 1027168

Other (OTH) AF: 0.000368 AC: 20 AN: 54326

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00692 AC: 709 AN: 102384 Hom.: 4 Cov.: 25 AF XY: 0.00691 AC XY: 340 AN XY: 49188

African (AFR) AF: 0.0209 AC: 525 AN: 25068

American (AMR) AF: 0.00670 AC: 76 AN: 11346

Ashkenazi Jewish (ASJ) AF: 0.00210 AC: 5 AN: 2384

East Asian (EAS) AF: 0.00 AC: 0 AN: 3974

South Asian (SAS) AF: 0.000551 AC: 2 AN: 3628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6250

Middle Eastern (MID) AF: 0.00685 AC: 1 AN: 146

European-Non Finnish (NFE) AF: 0.00177 AC: 84 AN: 47562

Other (OTH) AF: 0.0104 AC: 15 AN: 1436

Alfa AF: 0.000328 Hom.: 20

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

EPG5-related disorder Benign:1

May 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Sep 01, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Vici syndrome Benign:1

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.33

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11333207; hg19: chr18-43445730;