Genetic Variant NM_133180.3:c.431C>G (chr19-55080773-C-G) – 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.431C>G(p.Ala144Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 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: 0.00012 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EPS8L1
NM_133180.3 missense, splice_region

Scores

Splicing: ADA: 0.05046

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: 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=0.0075941086).

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>G	p.Ala144Gly	missense splice_region	Exon 7 of 20	NP_573441.2	Q8TE68-1
	EPS8L1	NM_017729.4		c.50C>G	p.Ala17Gly	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>G	p.Ala144Gly	missense splice_region	Exon 7 of 20	ENSP00000201647.5	Q8TE68-1
EPS8L1	ENST00000245618.5	TSL:1	c.50C>G	p.Ala17Gly	missense splice_region	Exon 2 of 15	ENSP00000245618.4	Q8TE68-2
EPS8L1	ENST00000587786.5	TSL:1	n.317C>G		splice_region non_coding_transcript_exon	Exon 5 of 14	ENSP00000465830.1	K7EKX9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00149

AC:

322

AN:

216734

AF XY:

0.000892

show subpopulations

Gnomad AFR exome

AF:

0.0115

Gnomad AMR exome

AF:

0.000392

Gnomad ASJ exome

AF:

0.000315

Gnomad EAS exome

AF:

0.00138

Gnomad FIN exome

AF:

0.000887

Gnomad NFE exome

AF:

0.00133

Gnomad OTH exome

AF:

0.000725

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000118

AC:

171

AN:

1444798

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

717682

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000608

AC:

AN:

32886

American (AMR)

AF:

0.000170

AC:

AN:

41150

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25926

East Asian (EAS)

AF:

0.00

AC:

AN:

38214

South Asian (SAS)

AF:

0.00

AC:

AN:

84888

European-Finnish (FIN)

AF:

0.00305

AC:

155

AN:

50820

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5468

European-Non Finnish (NFE)

AF:

0.00000452

AC:

AN:

1105716

Other (OTH)

AF:

0.0000335

AC:

AN:

59730

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.388

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00474

AC:

568

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

0.0012

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0076

MetaSVM

Benign

-0.49

MutationAssessor

Uncertain

2.7

PhyloP100

3.0

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.32

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.018

Polyphen

0.96

Vest4

0.48

MVP

0.62

MPC

0.91

ClinPred

0.035

GERP RS

2.6

PromoterAI

-0.18

Neutral

(source)

Varity_R

0.42

gMVP

0.52

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.050

dbscSNV1_RF

Benign

0.28

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.20

Position offset: -1

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