dbSNP rs371897669: EPS15L1:p.Pro777Ser (chr19-16377173-G-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4BS2

The NM_001258374.3(EPS15L1):c.2329C>T(p.Pro777Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P777A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

EPS15L1
NM_001258374.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.44

Publications

0 publications found

Variant links:

Genes affected

EPS15L1 (HGNC:24634): (epidermal growth factor receptor pathway substrate 15 like 1) Enables cadherin binding activity. Predicted to be involved in endocytosis and endosomal transport. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

EPS15L1 Gene-Disease associations (from GenCC):

split hand-foot malformation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

EPS15L1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4052425).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPS15L1	NM_001258374.3 link	c.2329C>T	p.Pro777Ser	missense_variant	Exon 22 of 24	ENST00000455140.7	NP_001245303.1	Q9UBC2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPS15L1	ENST00000455140.7 link	c.2329C>T	p.Pro777Ser	missense_variant	Exon 22 of 24	2	NM_001258374.3	ENSP00000393313.1		Q9UBC2-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

249766

AF XY:

0.00000740

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000294

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460520

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726576

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33414

American (AMR)

AF:

0.0000449

AC:

AN:

44506

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39554

South Asian (SAS)

AF:

0.00

AC:

AN:

86056

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111408

Other (OTH)

AF:

0.00

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.27

.;T

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.075

MetaRNN

Benign

0.41

T;T

MetaSVM

Benign

-0.29

MutationAssessor

Uncertain

2.5

M;M

PhyloP100

6.4

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-4.8

D;D

REVEL

Benign

0.27

Sift

Uncertain

0.017

D;D

Sift4G

Benign

0.13

T;T

Polyphen

1.0

.;D

Vest4

0.53

MutPred

0.17

Gain of phosphorylation at P777 (P = 0.0073);Gain of phosphorylation at P777 (P = 0.0073);

MVP

0.56

MPC

0.24

ClinPred

0.97

GERP RS

4.6

Varity_R

0.56

gMVP

0.47

Mutation Taster

=68/32

polymorphism

(source)

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

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rs371897669

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over