Genetic Variant NM_133180.3:c.389C>A (chr19-55080238-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_133180.3(EPS8L1):c.389C>A(p.Ala130Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A130P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

EPS8L1
NM_133180.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.104

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05068168).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133180.3. 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
	EPS8L1	NM_133180.3	MANE Select	c.389C>A	p.Ala130Glu	missense	Exon 6 of 20	NP_573441.2	Q8TE68-1
	EPS8L1	NM_017729.4		c.-256C>A		upstream_gene	N/A	NP_060199.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPS8L1	ENST00000201647.11	TSL:1 MANE Select	c.389C>A	p.Ala130Glu	missense	Exon 6 of 20	ENSP00000201647.5	Q8TE68-1
EPS8L1	ENST00000587786.5	TSL:1	n.275C>A		non_coding_transcript_exon	Exon 4 of 14	ENSP00000465830.1	K7EKX9
EPS8L1	ENST00000592824.5	TSL:1	n.493C>A		non_coding_transcript_exon	Exon 6 of 15

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.23e-7

AC:

AN:

1383338

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

679358

show subpopulations

African (AFR)

AF:

0.0000319

AC:

AN:

31324

American (AMR)

AF:

0.00

AC:

AN:

35022

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24786

East Asian (EAS)

AF:

0.00

AC:

AN:

35384

South Asian (SAS)

AF:

0.00

AC:

AN:

78446

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5448

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1068214

Other (OTH)

AF:

0.00

AC:

AN:

57140

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0044

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.71

M_CAP

Benign

0.056

MetaRNN

Benign

0.051

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PhyloP100

0.10

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.74

REVEL

Benign

0.067

Sift

Benign

0.22

Sift4G

Benign

0.82

Polyphen

0.23

Vest4

0.19

MutPred

0.45

Gain of disorder (P = 0.023)

MVP

0.26

MPC

0.52

ClinPred

0.11

GERP RS

2.8

PromoterAI

-0.12

Neutral

(source)

Varity_R

0.15

gMVP

0.19

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over