17-50537022-C-G

Position:

• chr17-50537022-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017957.3(EPN3):​c.466C>G​(p.Leu156Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,946 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EPN3 NM_017957.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.783

Genes affected

EPN3 (HGNC:18235): (epsin 3) Predicted to enable clathrin binding activity and phospholipid binding activity. Predicted to be involved in endocytosis. Located in clathrin-coated vesicle; nucleoplasm; and perinuclear region of cytoplasm. Is extrinsic component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14821342).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPN3	NM_017957.3	c.466C>G	p.Leu156Val	missense_variant	2/10	ENST00000268933.8	NP_060427.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPN3	ENST00000268933.8	c.466C>G	p.Leu156Val	missense_variant	2/10	2	NM_017957.3	ENSP00000268933	P1
	ENST00000654456.1	n.482+905G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460946 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726820

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2022

The c.466C>G (p.L156V) alteration is located in exon 2 (coding exon 1) of the EPN3 gene. This alteration results from a C to G substitution at nucleotide position 466, causing the leucine (L) at amino acid position 156 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.062	T;T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.5	M;.;.
MutationTaster	Benign	0.97	N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.53	N;N;.
REVEL	Benign	0.10
Sift	Benign	0.15	T;T;.
Sift4G	Benign	0.20	T;T;T
Polyphen		0.56	P;.;.
Vest4		0.37
MVP		0.59
MPC		0.19
ClinPred		0.36	T
GERP RS		3.5
Varity_R		0.085
gMVP		0.12

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-48614383;