18-45865765-CAAAAAAA-CAAA

Variant names:

• chr18-45865765-CAAAA-C
• rs11333207
• NM_020964.3:c.6622-10_6622-7delTTTT

Variant summary

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

The NM_020964.3(EPG5):​c.6622-10_6622-7delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000214 in 1,407,098 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 25)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: EPG5 NM_020964.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.635
• 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.

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.6622-10_6622-7delTTTT		splice_region intron	N/A	NP_066015.2	Q9HCE0-1
	EPG5	NM_001410859.1		c.6619-10_6619-7delTTTT		splice_region intron	N/A	NP_001397788.1	A0A8Q3SIU6
	EPG5	NM_001410858.1		c.6622-10_6622-7delTTTT		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.6622-10_6622-7delTTTT		splice_region intron	N/A	ENSP00000282041.4	Q9HCE0-1
	EPG5	ENST00000587884.2	TSL:1	n.*2362-10_*2362-7delTTTT		splice_region intron	N/A	ENSP00000466990.2	K7ENK5
	EPG5	ENST00000590884.6	TSL:1	n.*934-10_*934-7delTTTT		splice_region intron	N/A	ENSP00000466403.2	K7EM87

Frequencies

GnomAD3 genomes AF: 0.0000390 AC: 4 AN: 102552 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.0000795

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000210

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000228 AC: 297 AN: 1304536 Hom.: 0 AF XY: 0.000243 AC XY: 157 AN XY: 645178

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

African (AFR) AF: 0.000354 AC: 10 AN: 28250

American (AMR) AF: 0.000847 AC: 26 AN: 30680

Ashkenazi Jewish (ASJ) AF: 0.000535 AC: 11 AN: 20554

East Asian (EAS) AF: 0.000321 AC: 12 AN: 37400

South Asian (SAS) AF: 0.000443 AC: 30 AN: 67764

European-Finnish (FIN) AF: 0.000642 AC: 24 AN: 37394

Middle Eastern (MID) AF: 0.000710 AC: 3 AN: 4224

European-Non Finnish (NFE) AF: 0.000163 AC: 167 AN: 1024028

Other (OTH) AF: 0.000258 AC: 14 AN: 54242

⚠️ 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: 0.0000390 AC: 4 AN: 102562 Hom.: 0 Cov.: 25 AF XY: 0.0000406 AC XY: 2 AN XY: 49284

African (AFR) AF: 0.0000794 AC: 2 AN: 25202

American (AMR) AF: 0.00 AC: 0 AN: 11374

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2386

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 3628

European-Finnish (FIN) AF: 0.000160 AC: 1 AN: 6248

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

European-Non Finnish (NFE) AF: 0.0000210 AC: 1 AN: 47566

Other (OTH) AF: 0.00 AC: 0 AN: 1440

Alfa AF: 0.00 Hom.: 20

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.64
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;