chr18-45865765-CAAA-C

Variant names:

• chr18-45865765-CAAA-C
• rs11333207
• NM_020964.3:c.6622-9_6622-7delTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_020964.3(EPG5):​c.6622-9_6622-7delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,391,886 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000029 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0020 (0 hom.)
• Consequence: EPG5 NM_020964.3 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.590
• 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.

• PM2: Variant has high frequency in the AMR (0.00735) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).
• BP6: Variant 18-45865765-CAAA-C is Benign according to our data. Variant chr18-45865765-CAAA-C is described in ClinVar as Benign. ClinVar VariationId is 775398.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.6622-9_6622-7delTTT		splice_region intron	N/A	NP_066015.2	Q9HCE0-1
	EPG5	NM_001410859.1		c.6619-9_6619-7delTTT		splice_region intron	N/A	NP_001397788.1	A0A8Q3SIU6
	EPG5	NM_001410858.1		c.6622-9_6622-7delTTT		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.6622-9_6622-7delTTT		splice_region intron	N/A	ENSP00000282041.4	Q9HCE0-1
	EPG5	ENST00000587884.2	TSL:1	n.*2362-9_*2362-7delTTT		splice_region intron	N/A	ENSP00000466990.2	K7ENK5
	EPG5	ENST00000590884.6	TSL:1	n.*934-9_*934-7delTTT		splice_region intron	N/A	ENSP00000466403.2	K7EM87

Frequencies

GnomAD3 genomes AF: 0.0000293 AC: 3 AN: 102534 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00

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: 0.000480

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00603 AC: 632 AN: 104766 AF XY: 0.00630

Gnomad AFR exome AF: 0.00447

Gnomad AMR exome AF: 0.0113

Gnomad ASJ exome AF: 0.00896

Gnomad EAS exome AF: 0.00777

Gnomad FIN exome AF: 0.00632

Gnomad NFE exome AF: 0.00378

Gnomad OTH exome AF: 0.00301

GnomAD4 exome AF: 0.00201 AC: 2596 AN: 1289352 Hom.: 0 AF XY: 0.00217 AC XY: 1384 AN XY: 637508

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

African (AFR) AF: 0.00218 AC: 61 AN: 27938

American (AMR) AF: 0.00818 AC: 248 AN: 30312

Ashkenazi Jewish (ASJ) AF: 0.00311 AC: 63 AN: 20226

East Asian (EAS) AF: 0.00334 AC: 123 AN: 36826

South Asian (SAS) AF: 0.00475 AC: 317 AN: 66730

European-Finnish (FIN) AF: 0.00344 AC: 127 AN: 36902

Middle Eastern (MID) AF: 0.00264 AC: 11 AN: 4166

European-Non Finnish (NFE) AF: 0.00152 AC: 1544 AN: 1012590

Other (OTH) AF: 0.00190 AC: 102 AN: 53662

⚠️ 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: 0.0000293 AC: 3 AN: 102534 Hom.: 0 Cov.: 25 AF XY: 0.0000406 AC XY: 2 AN XY: 49230

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

African (AFR) AF: 0.00 AC: 0 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: 0.000480 AC: 3 AN: 6250

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 47564

Other (OTH) AF: 0.00 AC: 0 AN: 1432

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0232839), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 20

ClinVar

ClinVar submissions

Significance: 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		0.59
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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;