Genetic Variant NM_133180.3:c.431C>A (chr19-55080773-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_133180.3(EPS8L1):c.431C>A(p.Ala144Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. A144V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

EPS8L1
NM_133180.3 missense, splice_region

Scores

Splicing: ADA: 0.03877

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.04

Publications

3 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.903

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.431C>A	p.Ala144Glu	missense splice_region	Exon 7 of 20	NP_573441.2	Q8TE68-1
	EPS8L1	NM_017729.4		c.50C>A	p.Ala17Glu	missense splice_region	Exon 2 of 15	NP_060199.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPS8L1	ENST00000201647.11	TSL:1 MANE Select	c.431C>A	p.Ala144Glu	missense splice_region	Exon 7 of 20	ENSP00000201647.5	Q8TE68-1
EPS8L1	ENST00000245618.5	TSL:1	c.50C>A	p.Ala17Glu	missense splice_region	Exon 2 of 15	ENSP00000245618.4	Q8TE68-2
EPS8L1	ENST00000587786.5	TSL:1	n.317C>A		splice_region non_coding_transcript_exon	Exon 5 of 14	ENSP00000465830.1	K7EKX9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000461

AC:

AN:

216734

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000104

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1444810

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717686

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32890

American (AMR)

AF:

0.00

AC:

AN:

41150

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25926

East Asian (EAS)

AF:

0.0000262

AC:

AN:

38216

South Asian (SAS)

AF:

0.00

AC:

AN:

84888

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50824

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5468

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105718

Other (OTH)

AF:

0.00

AC:

AN:

59730

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000834

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Uncertain

0.063

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.72

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.85

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.7

PhyloP100

3.0

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.33

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.56

MutPred

0.82

Gain of disorder (P = 0.0315)

MVP

0.66

MPC

1.0

ClinPred

1.0

GERP RS

2.6

PromoterAI

-0.074

Neutral

(source)

Varity_R

0.79

gMVP

0.86

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.039

dbscSNV1_RF

Benign

0.25

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.22

Position offset: 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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over