18-45954964-C-T

Variant names:

• chr18-45954964-C-T
• rs186410807
• NM_020964.3:c.438G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS1

The NM_020964.3(EPG5):​c.438G>A​(p.Ser146Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000593 in 1,613,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. S146S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00057 (0 hom.)
• Consequence: EPG5 NM_020964.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.0140
• 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 18-45954964-C-T is Benign according to our data. Variant chr18-45954964-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 534622.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.014 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000574 (839/1461698) while in subpopulation MID AF = 0.00312 (18/5766). AF 95% confidence interval is 0.00202. There are 0 homozygotes in GnomAdExome4. There are 388 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

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.438G>A	p.Ser146Ser	synonymous	Exon 2 of 44	NP_066015.2	Q9HCE0-1
	EPG5	NM_001410859.1		c.438G>A	p.Ser146Ser	synonymous	Exon 2 of 44	NP_001397788.1	A0A8Q3SIU6
	EPG5	NM_001410858.1		c.438G>A	p.Ser146Ser	synonymous	Exon 2 of 44	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.438G>A	p.Ser146Ser	synonymous	Exon 2 of 44	ENSP00000282041.4	Q9HCE0-1
	EPG5	ENST00000587884.2	TSL:1	n.438G>A		non_coding_transcript_exon	Exon 2 of 45	ENSP00000466990.2	K7ENK5
	EPG5	ENST00000587974.1	TSL:1	n.473G>A		non_coding_transcript_exon	Exon 2 of 24

Frequencies

GnomAD3 genomes AF: 0.000789 AC: 120 AN: 152030 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000546 AC: 136 AN: 249202 AF XY: 0.000533

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000495

Gnomad OTH exome AF: 0.000991

GnomAD4 exome AF: 0.000574 AC: 839 AN: 1461698 Hom.: 0 Cov.: 32 AF XY: 0.000534 AC XY: 388 AN XY: 727162

African (AFR) AF: 0.00176 AC: 59 AN: 33464

American (AMR) AF: 0.00134 AC: 60 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5766

European-Non Finnish (NFE) AF: 0.000564 AC: 627 AN: 1111948

Other (OTH) AF: 0.00119 AC: 72 AN: 60384

GnomAD4 genome AF: 0.000776 AC: 118 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.000834 AC XY: 62 AN XY: 74366

African (AFR) AF: 0.00125 AC: 52 AN: 41504

American (AMR) AF: 0.00177 AC: 27 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 67996

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.000687 Hom.: 0

Bravo AF: 0.00110

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	EPG5-related disorder (1)
-	-	1	Vici syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.5
DANN	Benign	0.43
PhyloP100		-0.014
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: rs186410807; hg19: chr18-43534930; COSMIC: COSV99956748;