18-45865765-CAAAAAAA-CAAAAAAAAAAAAAAAAAAA

Variant names:

• chr18-45865765-C-CAAAAAAAAAAAA
• rs11333207
• NM_020964.3:c.6622-18_6622-7dupTTTTTTTTTTTT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_020964.3(EPG5):​c.6622-18_6622-7dupTTTTTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000288 in 1,411,396 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 25)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: EPG5 NM_020964.3 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts 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: Benign. The variant received -12 ACMG points.

• BP6: Variant 18-45865765-C-CAAAAAAAAAAAA is Benign according to our data. Variant chr18-45865765-C-CAAAAAAAAAAAA is described in ClinVar as Likely_benign. ClinVar VariationId is 1127228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00254 (260/102452) while in subpopulation AFR AF = 0.00964 (242/25094). AF 95% confidence interval is 0.00865. There are 1 homozygotes in GnomAd4. There are 115 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.6622-18_6622-7dupTTTTTTTTTTTT		splice_region intron	N/A	NP_066015.2	Q9HCE0-1
	EPG5	NM_001410859.1		c.6619-18_6619-7dupTTTTTTTTTTTT		splice_region intron	N/A	NP_001397788.1	A0A8Q3SIU6
	EPG5	NM_001410858.1		c.6622-18_6622-7dupTTTTTTTTTTTT		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_6622-6insTTTTTTTTTTTT		splice_region intron	N/A	ENSP00000282041.4	Q9HCE0-1
	EPG5	ENST00000587884.2	TSL:1	n.*2362-7_*2362-6insTTTTTTTTTTTT		splice_region intron	N/A	ENSP00000466990.2	K7ENK5
	EPG5	ENST00000590884.6	TSL:1	n.*934-7_*934-6insTTTTTTTTTTTT		splice_region intron	N/A	ENSP00000466403.2	K7EM87

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 260 AN: 102440 Hom.: 1 Cov.: 25

Gnomad AFR AF: 0.00966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000616

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00279

GnomAD4 exome AF: 0.000112 AC: 146 AN: 1308944 Hom.: 0 Cov.: 0 AF XY: 0.000103 AC XY: 67 AN XY: 647370

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

African (AFR) AF: 0.00181 AC: 51 AN: 28244

American (AMR) AF: 0.000585 AC: 18 AN: 30780

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20626

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

South Asian (SAS) AF: 0.0000734 AC: 5 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: 0.0000584 AC: 60 AN: 1027434

Other (OTH) AF: 0.000184 AC: 10 AN: 54388

⚠️ 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: 0.00254 AC: 260 AN: 102452 Hom.: 1 Cov.: 25 AF XY: 0.00234 AC XY: 115 AN XY: 49238

African (AFR) AF: 0.00964 AC: 242 AN: 25094

American (AMR) AF: 0.000616 AC: 7 AN: 11370

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: 0.00 AC: 0 AN: 6252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 152

European-Non Finnish (NFE) AF: 0.000147 AC: 7 AN: 47566

Other (OTH) AF: 0.00278 AC: 4 AN: 1440

Alfa AF: 0.00 Hom.: 20

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (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;