Genetic Variant EPG5:c.6622-8_6622-7delTT (chr18-45865765-CAA-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP6_Moderate

The NM_020964.3(EPG5):c.6622-8_6622-7delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 1,346,102 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 25)

Exomes 𝑓: 0.028 ( 0 hom. )

Consequence

EPG5
NM_020964.3 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.590

Publications

3 publications found

Variant links:

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

EPG5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Variant has high frequency in the AMR (0.0863) population. However there is too low homozygotes in high coverage region: (expected more than 225, got 0).

BP6

Variant 18-45865765-CAA-C is Benign according to our data. Variant chr18-45865765-CAA-C is described in ClinVar as Benign. ClinVar VariationId is 770277.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPG5	NM_020964.3 link	c.6622-8_6622-7delTT		splice_region_variant, intron_variant	Intron 38 of 43	ENST00000282041.11	NP_066015.2	Q9HCE0-1Q9BTI0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPG5	ENST00000282041.11 link	c.6622-8_6622-7delTT		splice_region_variant, intron_variant	Intron 38 of 43	1	NM_020964.3	ENSP00000282041.4		Q9HCE0-1

Frequencies

GnomAD3 genomes

AF:

0.00138

AC:

141

AN:

102466

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00175

Gnomad SAS

AF:

0.000549

Gnomad FIN

AF:

0.00692

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.00140

GnomAD2 exomes

AF:

0.0556

AC:

5820

AN:

104766

AF XY:

0.0548

show subpopulations

Gnomad AFR exome

AF:

0.0342

Gnomad AMR exome

AF:

0.106

Gnomad ASJ exome

AF:

0.0538

Gnomad EAS exome

AF:

0.0817

Gnomad FIN exome

AF:

0.0500

Gnomad NFE exome

AF:

0.0348

Gnomad OTH exome

AF:

0.0594

GnomAD4 exome

AF:

0.0279

AC:

34670

AN:

1243628

Hom.:

AF XY:

0.0293

AC XY:

17999

AN XY:

614210

show subpopulations

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

African (AFR)

AF:

0.0230

AC:

619

AN:

26898

American (AMR)

AF:

0.0892

AC:

2600

AN:

29158

Ashkenazi Jewish (ASJ)

AF:

0.0365

AC:

711

AN:

19462

East Asian (EAS)

AF:

0.0745

AC:

2636

AN:

35364

South Asian (SAS)

AF:

0.0609

AC:

3892

AN:

63926

European-Finnish (FIN)

AF:

0.0423

AC:

1505

AN:

35592

Middle Eastern (MID)

AF:

0.0328

AC:

133

AN:

4056

European-Non Finnish (NFE)

AF:

0.0215

AC:

20991

AN:

977578

Other (OTH)

AF:

0.0307

AC:

1583

AN:

51594

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

3314

6628

9941

13255

16569

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

672

1344

2016

2688

3360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00140

AC:

143

AN:

102474

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

AN XY:

49228

show subpopulations

African (AFR)

AF:

0.000675

AC:

AN:

25188

American (AMR)

AF:

0.00132

AC:

AN:

11364

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2384

East Asian (EAS)

AF:

0.00176

AC:

AN:

3972

South Asian (SAS)

AF:

0.000552

AC:

AN:

3626

European-Finnish (FIN)

AF:

0.00692

AC:

AN:

6218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

154

European-Non Finnish (NFE)

AF:

0.00116

AC:

AN:

47540

Other (OTH)

AF:

0.00278

AC:

AN:

1438

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00115

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 16, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.59

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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18-45865765-CAAAAAAA-CAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over