chr18-45865765-CAA-C

Variant names:

• chr18-45865765-CAA-C
• rs11333207
• NM_020964.3:c.6622-8_6622-7delTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.590
• 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: 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.

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.6622-8_6622-7delTT		splice_region intron	N/A	NP_066015.2	Q9HCE0-1
	EPG5	NM_001410859.1		c.6619-8_6619-7delTT		splice_region intron	N/A	NP_001397788.1	A0A8Q3SIU6
	EPG5	NM_001410858.1		c.6622-8_6622-7delTT		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.6622-8_6622-7delTT		splice_region intron	N/A	ENSP00000282041.4	Q9HCE0-1
	EPG5	ENST00000587884.2	TSL:1	n.*2362-8_*2362-7delTT		splice_region intron	N/A	ENSP00000466990.2	K7ENK5
	EPG5	ENST00000590884.6	TSL:1	n.*934-8_*934-7delTT		splice_region intron	N/A	ENSP00000466403.2	K7EM87

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 141 AN: 102466 Hom.: 0 Cov.: 25

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

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.: 0 AF XY: 0.0293 AC XY: 17999 AN XY: 614210

⚠️ 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), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00140 AC: 143 AN: 102474 Hom.: 0 Cov.: 25 AF XY: 0.00152 AC XY: 75 AN XY: 49228

African (AFR) AF: 0.000675 AC: 17 AN: 25188

American (AMR) AF: 0.00132 AC: 15 AN: 11364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2384

East Asian (EAS) AF: 0.00176 AC: 7 AN: 3972

South Asian (SAS) AF: 0.000552 AC: 2 AN: 3626

European-Finnish (FIN) AF: 0.00692 AC: 43 AN: 6218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 154

European-Non Finnish (NFE) AF: 0.00116 AC: 55 AN: 47540

Other (OTH) AF: 0.00278 AC: 4 AN: 1438

Alfa AF: 0.00115 Hom.: 20

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.59
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs11333207; hg19: chr18-43445730;