18-45910574-G-C

Variant names:

• chr18-45910574-G-C
• rs200079588
• NM_020964.3:c.4152C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_020964.3(EPG5):​c.4152C>G​(p.His1384Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000481 in 1,613,792 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H1384H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (1 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.796
• Publications: 3 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013958991).
• BP6: Variant 18-45910574-G-C is Benign according to our data. Variant chr18-45910574-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 570618.

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.4152C>G	p.His1384Gln	missense	Exon 23 of 44	NP_066015.2	Q9HCE0-1
	EPG5	NM_001410859.1		c.4152C>G	p.His1384Gln	missense	Exon 23 of 44	NP_001397788.1	A0A8Q3SIU6
	EPG5	NM_001410858.1		c.4152C>G	p.His1384Gln	missense	Exon 23 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.4152C>G	p.His1384Gln	missense	Exon 23 of 44	ENSP00000282041.4	Q9HCE0-1
	EPG5	ENST00000587884.2	TSL:1	n.4152C>G		non_coding_transcript_exon	Exon 23 of 45	ENSP00000466990.2	K7ENK5
	EPG5	ENST00000587974.1	TSL:1	n.4187C>G		non_coding_transcript_exon	Exon 23 of 24

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000281 AC: 70 AN: 249268 AF XY: 0.000281

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000575

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000497 AC: 727 AN: 1461576 Hom.: 1 Cov.: 30 AF XY: 0.000477 AC XY: 347 AN XY: 727092

African (AFR) AF: 0.000119 AC: 4 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5608

European-Non Finnish (NFE) AF: 0.000633 AC: 704 AN: 1111936

Other (OTH) AF: 0.000265 AC: 16 AN: 60368

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74358

African (AFR) AF: 0.000193 AC: 8 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000491 Hom.: 0

Bravo AF: 0.000306

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000364 AC: 3

ExAC AF: 0.000323 AC: 39

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	1	-	Vici syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.6
DANN	Benign	0.64
DEOGEN2	Benign	0.0021	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.8	N
PhyloP100		0.80
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.022
Sift	Benign	0.72	T
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.095
MutPred		0.14		Gain of solvent accessibility (P = 0.0338)
MVP		0.061
MPC		0.15
ClinPred		0.0078	T
GERP RS		-0.032
Varity_R		0.036
gMVP		0.23
Mutation Taster		=85/15	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: rs200079588; hg19: chr18-43490539; COSMIC: COSV56351113;