NM_020964.3:c.6516C>T

Variant names:

• chr18-45866903-G-A
• rs114665741
• NM_020964.3:c.6516C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020964.3(EPG5):​c.6516C>T​(p.Tyr2172Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00288 in 1,613,970 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (25 hom.)
• Consequence: EPG5 NM_020964.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.824
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 18-45866903-G-A is Benign according to our data. Variant chr18-45866903-G-A is described in ClinVar as Benign. ClinVar VariationId is 534617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.824 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00897 (1366/152280) while in subpopulation AFR AF = 0.0254 (1054/41556). AF 95% confidence interval is 0.0241. There are 14 homozygotes in GnomAd4. There are 654 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPG5	NM_020964.3	MANE Select	c.6516C>T	p.Tyr2172Tyr	synonymous	Exon 38 of 44	NP_066015.2
	EPG5	NM_001410859.1		c.6513C>T	p.Tyr2171Tyr	synonymous	Exon 38 of 44	NP_001397788.1
	EPG5	NM_001410858.1		c.6516C>T	p.Tyr2172Tyr	synonymous	Exon 38 of 44	NP_001397787.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPG5	ENST00000282041.11	TSL:1 MANE Select	c.6516C>T	p.Tyr2172Tyr	synonymous	Exon 38 of 44	ENSP00000282041.4
	EPG5	ENST00000587884.2	TSL:1	n.*2256C>T		non_coding_transcript_exon	Exon 39 of 45	ENSP00000466990.2
	EPG5	ENST00000590884.6	TSL:1	n.*828C>T		non_coding_transcript_exon	Exon 36 of 42	ENSP00000466403.2

Frequencies

GnomAD3 genomes AF: 0.00894 AC: 1361 AN: 152162 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0253

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00400 AC: 997 AN: 249512 AF XY: 0.00348

Gnomad AFR exome AF: 0.0287

Gnomad AMR exome AF: 0.00698

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00202

Gnomad OTH exome AF: 0.00594

GnomAD4 exome AF: 0.00224 AC: 3276 AN: 1461690 Hom.: 25 Cov.: 32 AF XY: 0.00222 AC XY: 1616 AN XY: 727180

African (AFR) AF: 0.0267 AC: 893 AN: 33478

American (AMR) AF: 0.00693 AC: 310 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00253 AC: 66 AN: 26136

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

South Asian (SAS) AF: 0.000742 AC: 64 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.0215 AC: 124 AN: 5768

European-Non Finnish (NFE) AF: 0.00134 AC: 1494 AN: 1111818

Other (OTH) AF: 0.00537 AC: 324 AN: 60390

GnomAD4 genome AF: 0.00897 AC: 1366 AN: 152280 Hom.: 14 Cov.: 32 AF XY: 0.00878 AC XY: 654 AN XY: 74466

African (AFR) AF: 0.0254 AC: 1054 AN: 41556

American (AMR) AF: 0.0104 AC: 159 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00165 AC: 112 AN: 68022

Other (OTH) AF: 0.0104 AC: 22 AN: 2112

Alfa AF: 0.00740 Hom.: 8

Bravo AF: 0.0110

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00261

ClinVar

ClinVar submissions as Germline

Significance: 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	-0.49
CADD	Benign	2.3
DANN	Benign	0.40
PhyloP100		0.82
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: rs114665741; hg19: chr18-43446868;