Genetic Variant EPS15L1:p.Pro751Ser (chr19-16377251-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001258374.3(EPS15L1):c.2251C>T(p.Pro751Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

EPS15L1
NM_001258374.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.08

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08581719).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPS15L1	NM_001258374.3 link	c.2251C>T	p.Pro751Ser	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.2251C>T	p.Pro751Ser	missense_variant	Exon 22 of 24	2	NM_001258374.3	ENSP00000393313.1		Q9UBC2-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000404

AC:

AN:

247274

AF XY:

0.00000747

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1457988

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725508

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33134

American (AMR)

AF:

0.00

AC:

AN:

43306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26010

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39654

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85842

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5590

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110920

Other (OTH)

AF:

0.00

AC:

AN:

60196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 04, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2251C>T (p.P751S) alteration is located in exon 22 (coding exon 22) of the EPS15L1 gene. This alteration results from a C to T substitution at nucleotide position 2251, causing the proline (P) at amino acid position 751 to be replaced by a serine (S). 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

0.058

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.030

.;T

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.0067

MetaRNN

Benign

0.086

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;L

PhyloP100

1.1

PrimateAI

Benign

0.40

PROVEAN

Benign

0.67

N;N

REVEL

Benign

0.045

Sift

Benign

0.54

T;T

Sift4G

Benign

0.95

T;T

Polyphen

0.020

.;B

Vest4

0.32

MutPred

0.19

Gain of phosphorylation at P751 (P = 0.0093);Gain of phosphorylation at P751 (P = 0.0093);

MVP

0.47

MPC

0.096

ClinPred

0.13

GERP RS

3.5

Varity_R

0.053

gMVP

0.26

Mutation Taster

=96/4

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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19-16377251-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over