18-45855558-A-G

Variant names:

• chr18-45855558-A-G
• rs59817706
• NM_020964.3:c.7557+15T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020964.3(EPG5):​c.7557+15T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00245 in 1,600,232 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (35 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (50 hom.)
• Consequence: EPG5 NM_020964.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.134
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 18-45855558-A-G is Benign according to our data. Variant chr18-45855558-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445923.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 = 0.0124 (1887/152124) while in subpopulation AFR AF = 0.0433 (1798/41500). AF 95% confidence interval is 0.0417. There are 35 homozygotes in GnomAd4. There are 919 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

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.7557+15T>C		intron	N/A	NP_066015.2	Q9HCE0-1
	EPG5	NM_001410859.1		c.7554+15T>C		intron	N/A	NP_001397788.1	A0A8Q3SIU6
	EPG5	NM_001410858.1		c.7557+15T>C		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.7557+15T>C		intron	N/A	ENSP00000282041.4	Q9HCE0-1
	EPG5	ENST00000587884.2	TSL:1	n.*3297+15T>C		intron	N/A	ENSP00000466990.2	K7ENK5
	EPG5	ENST00000590884.6	TSL:1	n.*1869+15T>C		intron	N/A	ENSP00000466403.2	K7EM87

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1882 AN: 152006 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00865

GnomAD2 exomes AF: 0.00317 AC: 786 AN: 247794 AF XY: 0.00235

Gnomad AFR exome AF: 0.0466

Gnomad AMR exome AF: 0.00140

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000134

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00140 AC: 2031 AN: 1448108 Hom.: 50 Cov.: 27 AF XY: 0.00120 AC XY: 864 AN XY: 720554

African (AFR) AF: 0.0482 AC: 1601 AN: 33222

American (AMR) AF: 0.00186 AC: 83 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25984

East Asian (EAS) AF: 0.00 AC: 0 AN: 39544

South Asian (SAS) AF: 0.000175 AC: 15 AN: 85832

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53324

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5744

European-Non Finnish (NFE) AF: 0.000148 AC: 163 AN: 1099958

Other (OTH) AF: 0.00265 AC: 159 AN: 59936

GnomAD4 genome AF: 0.0124 AC: 1887 AN: 152124 Hom.: 35 Cov.: 32 AF XY: 0.0124 AC XY: 919 AN XY: 74380

African (AFR) AF: 0.0433 AC: 1798 AN: 41500

American (AMR) AF: 0.00393 AC: 60 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67978

Other (OTH) AF: 0.00856 AC: 18 AN: 2104

Alfa AF: 0.00649 Hom.: 4

Bravo AF: 0.0147

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Vici syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.3
DANN	Benign	0.50
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs59817706; hg19: chr18-43435523;