Genetic Variant EPS8L1:p.Leu88Phe (chr19-55079834-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_133180.3(EPS8L1):c.262C>T(p.Leu88Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,766 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

EPS8L1
NM_133180.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.23

Variant links:

Genes affected

EPS8L1 (HGNC:21295): (EPS8 signaling adaptor L1) This gene encodes a protein that is related to epidermal growth factor receptor pathway substrate 8 (EPS8), a substrate for the epidermal growth factor receptor. The function of this protein is unknown. At least two alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

EPS8L1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPS8L1	NM_133180.3 link	c.262C>T	p.Leu88Phe	missense_variant	Exon 5 of 20	ENST00000201647.11	NP_573441.2	Q8TE68-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPS8L1	ENST00000201647.11 link	c.262C>T	p.Leu88Phe	missense_variant	Exon 5 of 20	1	NM_133180.3	ENSP00000201647.5		Q8TE68-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000162

AC:

AN:

247068

Hom.:

AF XY:

0.0000224

AC XY:

AN XY:

133856

show subpopulations

Gnomad AFR exome

AF:

0.0000630

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000269

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460766

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726614

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000313

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.262C>T (p.L88F) alteration is located in exon 5 (coding exon 4) of the EPS8L1 gene. This alteration results from a C to T substitution at nucleotide position 262, causing the leucine (L) at amino acid position 88 to be replaced by a phenylalanine (F). 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

0.22

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

T;T;T

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.72

T;T;T

M_CAP

Benign

0.060

MetaRNN

Uncertain

0.46

T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.7

.;L;.

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.1

.;N;N

REVEL

Benign

0.22

Sift

Benign

0.064

.;T;T

Sift4G

Benign

0.20

T;T;T

Polyphen

1.0

.;D;D

Vest4

0.38

MVP

0.36

MPC

0.85

ClinPred

0.76

GERP RS

4.0

Varity_R

0.15

gMVP

0.30

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over