chr18-45865765-C-CAAAAAAAAAAAAAAA

Variant names:

• chr18-45865765-C-CAAAAAAAAAAAAAAA
• rs11333207
• NM_020964.3:c.6622-21_6622-7dupTTTTTTTTTTTTTTT

Variant summary

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

The NM_020964.3(EPG5):​c.6622-21_6622-7dupTTTTTTTTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000567 in 1,411,844 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000098 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0000053 (0 hom.)
• Consequence: EPG5 NM_020964.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• 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: 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.6622-21_6622-7dupTTTTTTTTTTTTTTT		splice_region intron	N/A	NP_066015.2	Q9HCE0-1
	EPG5	NM_001410859.1		c.6619-21_6619-7dupTTTTTTTTTTTTTTT		splice_region intron	N/A	NP_001397788.1	A0A8Q3SIU6
	EPG5	NM_001410858.1		c.6622-21_6622-7dupTTTTTTTTTTTTTTT		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_6622-6insTTTTTTTTTTTTTTT		splice_region intron	N/A	ENSP00000282041.4	Q9HCE0-1
	EPG5	ENST00000587884.2	TSL:1	n.*2362-7_*2362-6insTTTTTTTTTTTTTTT		splice_region intron	N/A	ENSP00000466990.2	K7ENK5
	EPG5	ENST00000590884.6	TSL:1	n.*934-7_*934-6insTTTTTTTTTTTTTTT		splice_region intron	N/A	ENSP00000466403.2	K7EM87

Frequencies

GnomAD3 genomes AF: 0.00000975 AC: 1 AN: 102554 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.0000398

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000535 AC: 7 AN: 1309290 Hom.: 0 Cov.: 0 AF XY: 0.00000618 AC XY: 4 AN XY: 647536

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

African (AFR) AF: 0.000106 AC: 3 AN: 28370

American (AMR) AF: 0.0000325 AC: 1 AN: 30794

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20628

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 68130

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4242

European-Non Finnish (NFE) AF: 0.00000292 AC: 3 AN: 1027586

Other (OTH) AF: 0.00 AC: 0 AN: 54430

⚠️ 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: 0.00000975 AC: 1 AN: 102554 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 49248

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

African (AFR) AF: 0.0000398 AC: 1 AN: 25148

American (AMR) AF: 0.00 AC: 0 AN: 11364

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3992

South Asian (SAS) AF: 0.00 AC: 0 AN: 3644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 164

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 47580

Other (OTH) AF: 0.00 AC: 0 AN: 1434

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

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;