chr18-45865765-C-CAAAAAAAAA

Variant names:

• chr18-45865765-C-CAAAAAAAAA
• rs11333207
• NM_020964.3:c.6622-15_6622-7dupTTTTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_020964.3(EPG5):​c.6622-15_6622-7dupTTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,411,546 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., cov: 25)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: EPG5 NM_020964.3 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• 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: ClinGen, G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 18-45865765-C-CAAAAAAAAA is Benign according to our data. Variant chr18-45865765-C-CAAAAAAAAA is described in ClinVar as Likely_benign. ClinVar VariationId is 1651997.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00078 (80/102562) while in subpopulation AFR AF = 0.00302 (76/25194). AF 95% confidence interval is 0.00247. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.

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.6622-15_6622-7dupTTTTTTTTT		splice_region intron	N/A	NP_066015.2	Q9HCE0-1
	EPG5	NM_001410859.1		c.6619-15_6619-7dupTTTTTTTTT		splice_region intron	N/A	NP_001397788.1	A0A8Q3SIU6
	EPG5	NM_001410858.1		c.6622-15_6622-7dupTTTTTTTTT		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.6622-7_6622-6insTTTTTTTTT		splice_region intron	N/A	ENSP00000282041.4	Q9HCE0-1
	EPG5	ENST00000587884.2	TSL:1	n.*2362-7_*2362-6insTTTTTTTTT		splice_region intron	N/A	ENSP00000466990.2	K7ENK5
	EPG5	ENST00000590884.6	TSL:1	n.*934-7_*934-6insTTTTTTTTT		splice_region intron	N/A	ENSP00000466403.2	K7EM87

Frequencies

GnomAD3 genomes AF: 0.000780 AC: 80 AN: 102552 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000264

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000642 AC: 84 AN: 1308984 Hom.: 0 Cov.: 0 AF XY: 0.0000602 AC XY: 39 AN XY: 647394

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

African (AFR) AF: 0.00124 AC: 35 AN: 28234

American (AMR) AF: 0.000195 AC: 6 AN: 30782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20620

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 68128

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

Middle Eastern (MID) AF: 0.000472 AC: 2 AN: 4234

European-Non Finnish (NFE) AF: 0.0000302 AC: 31 AN: 1027482

Other (OTH) AF: 0.000184 AC: 10 AN: 54394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000176303), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000780 AC: 80 AN: 102562 Hom.: 0 Cov.: 25 AF XY: 0.000832 AC XY: 41 AN XY: 49282

African (AFR) AF: 0.00302 AC: 76 AN: 25194

American (AMR) AF: 0.000264 AC: 3 AN: 11376

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: 6252

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 47568

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

Alfa AF: 0.00 Hom.: 20

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	EPG5-related disorder (1)
-	-	1	Vici syndrome (1)

Computational scores

Source: dbNSFP v4.9

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

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;