18-45865765-CAAAAAAA-CAAAAAAAAAAAAAAAAAAAA

Variant names:

• chr18-45865765-C-CAAAAAAAAAAAAA
• rs11333207
• NM_020964.3:c.6622-19_6622-7dupTTTTTTTTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_020964.3(EPG5):​c.6622-19_6622-7dupTTTTTTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000475 in 1,411,738 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00020 (0 hom., cov: 25)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: EPG5 NM_020964.3 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -2 ACMG points.

• BP6: Variant 18-45865765-C-CAAAAAAAAAAAAA is Benign according to our data. Variant chr18-45865765-C-CAAAAAAAAAAAAA is described in ClinVar as Likely_benign. ClinVar VariationId is 2077447.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.6622-19_6622-7dupTTTTTTTTTTTTT		splice_region intron	N/A	NP_066015.2	Q9HCE0-1
	EPG5	NM_001410859.1		c.6619-19_6619-7dupTTTTTTTTTTTTT		splice_region intron	N/A	NP_001397788.1	A0A8Q3SIU6
	EPG5	NM_001410858.1		c.6622-19_6622-7dupTTTTTTTTTTTTT		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_6622-6insTTTTTTTTTTTTT		splice_region intron	N/A	ENSP00000282041.4	Q9HCE0-1
	EPG5	ENST00000587884.2	TSL:1	n.*2362-7_*2362-6insTTTTTTTTTTTTT		splice_region intron	N/A	ENSP00000466990.2	K7ENK5
	EPG5	ENST00000590884.6	TSL:1	n.*934-7_*934-6insTTTTTTTTTTTTT		splice_region intron	N/A	ENSP00000466403.2	K7EM87

Frequencies

GnomAD3 genomes AF: 0.000205 AC: 21 AN: 102544 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000756

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000176

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000351 AC: 46 AN: 1309184 Hom.: 0 Cov.: 0 AF XY: 0.0000340 AC XY: 22 AN XY: 647488

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

African (AFR) AF: 0.000883 AC: 25 AN: 28326

American (AMR) AF: 0.0000325 AC: 1 AN: 30788

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

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

South Asian (SAS) AF: 0.0000147 AC: 1 AN: 68130

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4238

European-Non Finnish (NFE) AF: 0.0000146 AC: 15 AN: 1027542

Other (OTH) AF: 0.0000735 AC: 4 AN: 54424

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000466493), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000205 AC: 21 AN: 102554 Hom.: 0 Cov.: 25 AF XY: 0.000223 AC XY: 11 AN XY: 49278

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

African (AFR) AF: 0.000754 AC: 19 AN: 25186

American (AMR) AF: 0.000176 AC: 2 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: 0.00 AC: 0 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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000197819), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 20

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Vici syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.33

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;