18-45865765-C-A

Variant names:

• chr18-45865765-C-A
• rs1309916888
• NM_020964.3:c.6622-6G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_020964.3(EPG5):​c.6622-6G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00666 in 1,306,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0039 (0 hom., cov: 21)
  • Exomes 𝑓: 0.0067 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EPG5 NM_020964.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001476
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.245
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Variant has high frequency in the SAS (0.018) population. However there is too low homozygotes in high coverage region: (expected more than 14, got 0).
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 18-45865765-C-A is Benign according to our data. Variant chr18-45865765-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 466262.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPG5	NM_020964.3	c.6622-6G>T		splice_region_variant, intron_variant	Intron 38 of 43	ENST00000282041.11	NP_066015.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPG5	ENST00000282041.11	c.6622-6G>T		splice_region_variant, intron_variant	Intron 38 of 43	1	NM_020964.3	ENSP00000282041.4

Frequencies

GnomAD3 genomes AF: 0.00385 AC: 392 AN: 101754 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00429

Gnomad AMI AF: 0.0103

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00169

Gnomad EAS AF: 0.00201

Gnomad SAS AF: 0.00220

Gnomad FIN AF: 0.00786

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00397

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0153 AC: 1598 AN: 104766 AF XY: 0.0149

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.0148

Gnomad ASJ exome AF: 0.0321

Gnomad EAS exome AF: 0.0196

Gnomad FIN exome AF: 0.0170

Gnomad NFE exome AF: 0.0138

Gnomad OTH exome AF: 0.0241

GnomAD4 exome AF: 0.00666 AC: 8710 AN: 1306956 Hom.: 0 Cov.: 31 AF XY: 0.00752 AC XY: 4857 AN XY: 646222

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

African (AFR) AF: 0.00809 AC: 229 AN: 28308

American (AMR) AF: 0.0175 AC: 537 AN: 30700

Ashkenazi Jewish (ASJ) AF: 0.0158 AC: 325 AN: 20570

East Asian (EAS) AF: 0.00990 AC: 371 AN: 37482

South Asian (SAS) AF: 0.0189 AC: 1276 AN: 67662

European-Finnish (FIN) AF: 0.0124 AC: 464 AN: 37430

Middle Eastern (MID) AF: 0.00734 AC: 31 AN: 4226

European-Non Finnish (NFE) AF: 0.00492 AC: 5052 AN: 1026252

Other (OTH) AF: 0.00782 AC: 425 AN: 54326

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00385 AC: 392 AN: 101764 Hom.: 0 Cov.: 21 AF XY: 0.00417 AC XY: 204 AN XY: 48958

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

African (AFR) AF: 0.00428 AC: 107 AN: 24986

American (AMR) AF: 0.00203 AC: 23 AN: 11346

Ashkenazi Jewish (ASJ) AF: 0.00169 AC: 4 AN: 2366

East Asian (EAS) AF: 0.00202 AC: 8 AN: 3966

South Asian (SAS) AF: 0.00221 AC: 8 AN: 3618

European-Finnish (FIN) AF: 0.00786 AC: 49 AN: 6232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 154

European-Non Finnish (NFE) AF: 0.00397 AC: 187 AN: 47088

Other (OTH) AF: 0.00 AC: 0 AN: 1428

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00729 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Vici syndrome Benign:1

Apr 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.5
DANN	Benign	0.49
PhyloP100		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.0080
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: rs1309916888; hg19: chr18-43445730; COSMIC: COSV56351373;