NM_020964.3:c.5954G>A

Variant names:

• chr18-45876331-C-T
• rs34674177
• NM_020964.3:c.5954G>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.5954G>A​(p.Arg1985Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00365 in 1,613,746 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. R1985W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (33 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (34 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.28
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002965033).
• BP6: Variant 18-45876331-C-T is Benign according to our data. Variant chr18-45876331-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 466260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0124 (1882/152234) while in subpopulation AFR AF = 0.0368 (1527/41540). AF 95% confidence interval is 0.0352. There are 33 homozygotes in GnomAd4. There are 892 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 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.5954G>A	p.Arg1985Gln	missense	Exon 35 of 44	NP_066015.2
	EPG5	NM_001410859.1		c.5951G>A	p.Arg1984Gln	missense	Exon 35 of 44	NP_001397788.1
	EPG5	NM_001410858.1		c.5954G>A	p.Arg1985Gln	missense	Exon 35 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.5954G>A	p.Arg1985Gln	missense	Exon 35 of 44	ENSP00000282041.4
	EPG5	ENST00000587884.2	TSL:1	n.*1694G>A		non_coding_transcript_exon	Exon 36 of 45	ENSP00000466990.2
	EPG5	ENST00000587884.2	TSL:1	n.*1694G>A		3_prime_UTR	Exon 36 of 45	ENSP00000466990.2

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1872 AN: 152116 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.0366

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.00501 AC: 1251 AN: 249564 AF XY: 0.00428

Gnomad AFR exome AF: 0.0413

Gnomad AMR exome AF: 0.00788

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00228

Gnomad OTH exome AF: 0.00693

GnomAD4 exome AF: 0.00274 AC: 4003 AN: 1461512 Hom.: 34 Cov.: 30 AF XY: 0.00265 AC XY: 1924 AN XY: 727076

African (AFR) AF: 0.0394 AC: 1319 AN: 33470

American (AMR) AF: 0.00774 AC: 346 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00253 AC: 66 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000603 AC: 52 AN: 86246

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53412

Middle Eastern (MID) AF: 0.0215 AC: 124 AN: 5766

European-Non Finnish (NFE) AF: 0.00158 AC: 1762 AN: 1111694

Other (OTH) AF: 0.00548 AC: 331 AN: 60374

GnomAD4 genome AF: 0.0124 AC: 1882 AN: 152234 Hom.: 33 Cov.: 32 AF XY: 0.0120 AC XY: 892 AN XY: 74422

African (AFR) AF: 0.0368 AC: 1527 AN: 41540

American (AMR) AF: 0.0118 AC: 180 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00185 AC: 126 AN: 68012

Other (OTH) AF: 0.0142 AC: 30 AN: 2110

Alfa AF: 0.00575 Hom.: 25

Bravo AF: 0.0146

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.0376 AC: 149

ESP6500EA AF: 0.00216 AC: 18

ExAC AF: 0.00556 AC: 672

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00279

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 11, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Vici syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.011	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.3
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.090
Sift	Benign	0.38	T
Sift4G	Benign	0.24	T
Polyphen		0.97	D
Vest4		0.18
MVP		0.43
MPC		0.22
ClinPred		0.018	T
GERP RS		5.9
Varity_R		0.11
gMVP		0.20
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs34674177; hg19: chr18-43456296;