18-45951220-C-T

Variant names:

• chr18-45951220-C-T
• rs117817123
• NM_020964.3:c.1271G>A

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.1271G>A​(p.Ser424Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,560,870 control chromosomes in the GnomAD database, including 175 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S424G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0098 (11 hom., cov: 33)
  • Exomes 𝑓: 0.013 (164 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.51
• Publications: 9 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 (MetaRNN=0.002789408).
• BP6: Variant 18-45951220-C-T is Benign according to our data. Variant chr18-45951220-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 466236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00979 (1491/152280) while in subpopulation SAS AF = 0.0168 (81/4826). AF 95% confidence interval is 0.0138. There are 11 homozygotes in GnomAd4. There are 700 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.1271G>A	p.Ser424Asn	missense	Exon 4 of 44	NP_066015.2	Q9HCE0-1
	EPG5	NM_001410859.1		c.1271G>A	p.Ser424Asn	missense	Exon 4 of 44	NP_001397788.1	A0A8Q3SIU6
	EPG5	NM_001410858.1		c.1271G>A	p.Ser424Asn	missense	Exon 4 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.1271G>A	p.Ser424Asn	missense	Exon 4 of 44	ENSP00000282041.4	Q9HCE0-1
	EPG5	ENST00000587884.2	TSL:1	n.1271G>A		non_coding_transcript_exon	Exon 4 of 45	ENSP00000466990.2	K7ENK5
	EPG5	ENST00000587974.1	TSL:1	n.1306G>A		non_coding_transcript_exon	Exon 4 of 24

Frequencies

GnomAD3 genomes AF: 0.00981 AC: 1492 AN: 152162 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0129

Gnomad ASJ AF: 0.0352

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.00255

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0110 AC: 2370 AN: 215610 AF XY: 0.0114

Gnomad AFR exome AF: 0.00275

Gnomad AMR exome AF: 0.00725

Gnomad ASJ exome AF: 0.0363

Gnomad EAS exome AF: 0.0000652

Gnomad FIN exome AF: 0.00361

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.0141

GnomAD4 exome AF: 0.0130 AC: 18336 AN: 1408590 Hom.: 164 Cov.: 30 AF XY: 0.0132 AC XY: 9233 AN XY: 698372

African (AFR) AF: 0.00272 AC: 86 AN: 31656

American (AMR) AF: 0.00865 AC: 317 AN: 36658

Ashkenazi Jewish (ASJ) AF: 0.0344 AC: 856 AN: 24910

East Asian (EAS) AF: 0.0000798 AC: 3 AN: 37584

South Asian (SAS) AF: 0.0182 AC: 1346 AN: 74088

European-Finnish (FIN) AF: 0.00423 AC: 217 AN: 51316

Middle Eastern (MID) AF: 0.0206 AC: 114 AN: 5538

European-Non Finnish (NFE) AF: 0.0134 AC: 14582 AN: 1088570

Other (OTH) AF: 0.0140 AC: 815 AN: 58270

GnomAD4 genome AF: 0.00979 AC: 1491 AN: 152280 Hom.: 11 Cov.: 33 AF XY: 0.00940 AC XY: 700 AN XY: 74448

African (AFR) AF: 0.00327 AC: 136 AN: 41564

American (AMR) AF: 0.0129 AC: 197 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0352 AC: 122 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0168 AC: 81 AN: 4826

European-Finnish (FIN) AF: 0.00255 AC: 27 AN: 10598

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0129 AC: 880 AN: 68026

Other (OTH) AF: 0.0189 AC: 40 AN: 2114

Alfa AF: 0.0128 Hom.: 18

Bravo AF: 0.0105

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00241 AC: 9

ESP6500EA AF: 0.0132 AC: 108

ExAC AF: 0.0102 AC: 1233

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	Vici syndrome (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Benign	0.82
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.0064
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.44	N
PhyloP100		1.5
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.30	N
REVEL	Benign	0.24
Sift	Benign	0.40	T
Sift4G	Benign	0.89	T
Polyphen		0.0040	B
Vest4		0.099
MPC		0.57
ClinPred		0.012	T
GERP RS		5.3
Varity_R		0.084
gMVP		0.063
Mutation Taster		=95/5	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: rs117817123; hg19: chr18-43531186; COSMIC: COSV56350000;