rs148683476

Variant names:

• chr18-45866897-C-T
• rs148683476
• NM_020964.3:c.6522G>A

Your query was ambiguous. Multiple possible variants found:

• chr18-45866897-C-T
• chr18-45866897-C-A

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.6522G>A​(p.Pro2174Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,613,994 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (8 hom., cov: 32)
  • Exomes 𝑓: 0.011 (103 hom.)
• Consequence: EPG5 NM_020964.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.13
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 18-45866897-C-T is Benign according to our data. Variant chr18-45866897-C-T is described in ClinVar as Benign. ClinVar VariationId is 534619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.13 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.007 (1066/152268) while in subpopulation NFE AF = 0.0116 (791/68022). AF 95% confidence interval is 0.011. There are 8 homozygotes in GnomAd4. There are 504 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.6522G>A	p.Pro2174Pro	synonymous	Exon 38 of 44	NP_066015.2	Q9HCE0-1
	EPG5	NM_001410859.1		c.6519G>A	p.Pro2173Pro	synonymous	Exon 38 of 44	NP_001397788.1	A0A8Q3SIU6
	EPG5	NM_001410858.1		c.6522G>A	p.Pro2174Pro	synonymous	Exon 38 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.6522G>A	p.Pro2174Pro	synonymous	Exon 38 of 44	ENSP00000282041.4	Q9HCE0-1
	EPG5	ENST00000587884.2	TSL:1	n.*2262G>A		non_coding_transcript_exon	Exon 39 of 45	ENSP00000466990.2	K7ENK5
	EPG5	ENST00000590884.6	TSL:1	n.*834G>A		non_coding_transcript_exon	Exon 36 of 42	ENSP00000466403.2	K7EM87

Frequencies

GnomAD3 genomes AF: 0.00701 AC: 1066 AN: 152150 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00677 AC: 1688 AN: 249492 AF XY: 0.00699

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.00295

Gnomad ASJ exome AF: 0.00457

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00515

Gnomad NFE exome AF: 0.00996

Gnomad OTH exome AF: 0.00643

GnomAD4 exome AF: 0.0106 AC: 15527 AN: 1461726 Hom.: 103 Cov.: 32 AF XY: 0.0105 AC XY: 7654 AN XY: 727182

African (AFR) AF: 0.00149 AC: 50 AN: 33476

American (AMR) AF: 0.00329 AC: 147 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00532 AC: 139 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00685 AC: 591 AN: 86258

European-Finnish (FIN) AF: 0.00490 AC: 262 AN: 53420

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.0122 AC: 13613 AN: 1111858

Other (OTH) AF: 0.0118 AC: 714 AN: 60388

GnomAD4 genome AF: 0.00700 AC: 1066 AN: 152268 Hom.: 8 Cov.: 32 AF XY: 0.00677 AC XY: 504 AN XY: 74450

African (AFR) AF: 0.00219 AC: 91 AN: 41536

American (AMR) AF: 0.00471 AC: 72 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00622 AC: 30 AN: 4826

European-Finnish (FIN) AF: 0.00471 AC: 50 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0116 AC: 791 AN: 68022

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.00945 Hom.: 1

Bravo AF: 0.00657

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0125

EpiControl AF: 0.0103

ClinVar

ClinVar submissions

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	-0.61
CADD	Benign	0.061
DANN	Benign	0.45
PhyloP100		-3.1
Mutation Taster		=78/22	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: rs148683476; hg19: chr18-43446862; COSMIC: COSV56346655;