18-45865765-CAAAAAAA-CAAAAAA

Variant names:

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

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.6622-7delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 102,434 control chromosomes in the GnomAD database, including 1,636 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (1636 hom., cov: 25)
  • Exomes 𝑓: 0.33 (184 hom.)
  • Failed GnomAD Quality Control
• Consequence: EPG5 NM_020964.3 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• 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-CA-C is Benign according to our data. Variant chr18-45865765-CA-C is described in ClinVar as Benign. ClinVar VariationId is 402832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPG5	NM_020964.3	c.6622-7delT		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.6622-7delT		splice_region_variant, intron_variant	Intron 38 of 43	1	NM_020964.3	ENSP00000282041.4

Frequencies

GnomAD3 genomes AF: 0.193 AC: 19781 AN: 102424 Hom.: 1634 Cov.: 25

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.0983

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.400

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.189

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.198

GnomAD2 exomes AF: 0.371 AC: 38881 AN: 104766 AF XY: 0.367

Gnomad AFR exome AF: 0.356

Gnomad AMR exome AF: 0.392

Gnomad ASJ exome AF: 0.367

Gnomad EAS exome AF: 0.386

Gnomad FIN exome AF: 0.366

Gnomad NFE exome AF: 0.366

Gnomad OTH exome AF: 0.369

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.329 AC: 378011 AN: 1150714 Hom.: 184 Cov.: 0 AF XY: 0.328 AC XY: 186861 AN XY: 569160

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

African (AFR) AF: 0.319 AC: 7804 AN: 24492

American (AMR) AF: 0.358 AC: 10024 AN: 27996

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 6320 AN: 18448

East Asian (EAS) AF: 0.408 AC: 13944 AN: 34208

South Asian (SAS) AF: 0.340 AC: 21212 AN: 62396

European-Finnish (FIN) AF: 0.338 AC: 11575 AN: 34220

Middle Eastern (MID) AF: 0.349 AC: 1335 AN: 3828

European-Non Finnish (NFE) AF: 0.323 AC: 289380 AN: 896776

Other (OTH) AF: 0.340 AC: 16417 AN: 48350

⚠️ 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: 0.193 AC: 19779 AN: 102434 Hom.: 1636 Cov.: 25 AF XY: 0.205 AC XY: 10072 AN XY: 49228

African (AFR) AF: 0.127 AC: 3210 AN: 25188

American (AMR) AF: 0.361 AC: 4106 AN: 11360

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 404 AN: 2382

East Asian (EAS) AF: 0.399 AC: 1590 AN: 3980

South Asian (SAS) AF: 0.343 AC: 1241 AN: 3620

European-Finnish (FIN) AF: 0.224 AC: 1393 AN: 6230

Middle Eastern (MID) AF: 0.182 AC: 28 AN: 154

European-Non Finnish (NFE) AF: 0.157 AC: 7464 AN: 47488

Other (OTH) AF: 0.198 AC: 285 AN: 1442

Alfa AF: 0.0344 Hom.: 20

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 39% of patients studied by a panel of primary immunodeficiencies. Number of patients: 37. Only high quality variants are reported. -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency - No homozygotes in ExAC -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Vici syndrome Benign:2

Jan 12, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: COSV56349940;