Genetic Variant ENTREP3:p.Ser464Ile (chr1-155250395-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006589.3(ENTREP3):c.1391G>T(p.Ser464Ile) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S464G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ENTREP3
NM_006589.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.813

Publications

0 publications found

Variant links:

Genes affected

ENTREP3 (HGNC:1233): (endosomal transmembrane epsin interactor 3) This gene is located near the gene for the lysosomal enzyme glucosylceramidase; a deficiency in this enzyme is associated with Gaucher disease. The encoded protein has been identified as a potential binding partner of a WW domain-containing protein which is involved in apoptosis and tumor suppression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2010]

ENTREP3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006589.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ENTREP3	NM_006589.3	MANE Select	c.1391G>T	p.Ser464Ile	missense	Exon 9 of 12	NP_006580.2
ENTREP3	NM_001267608.2		c.1337G>T	p.Ser446Ile	missense	Exon 8 of 11	NP_001254537.1	P81408-3
ENTREP3	NM_198264.2		c.1103G>T	p.Ser368Ile	missense	Exon 6 of 9	NP_937995.1	P81408-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ENTREP3	ENST00000361361.7	TSL:1 MANE Select	c.1391G>T	p.Ser464Ile	missense	Exon 9 of 12	ENSP00000354958.2	P81408-1
ENTREP3	ENST00000368368.7	TSL:1	c.1337G>T	p.Ser446Ile	missense	Exon 8 of 11	ENSP00000357352.3	P81408-3
ENTREP3	ENST00000350210.6	TSL:1	c.1103G>T	p.Ser368Ile	missense	Exon 6 of 9	ENSP00000307128.4	P81408-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000164

AC:

AN:

1219390

Hom.:

Cov.:

AF XY:

0.00000165

AC XY:

AN XY:

605392

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26892

American (AMR)

AF:

0.0000330

AC:

AN:

30280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21770

East Asian (EAS)

AF:

0.00

AC:

AN:

32644

South Asian (SAS)

AF:

0.00

AC:

AN:

74254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44930

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3594

European-Non Finnish (NFE)

AF:

0.00000107

AC:

AN:

934514

Other (OTH)

AF:

0.00

AC:

AN:

50512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.0000302

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0099

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Benign

0.76

M_CAP

Benign

0.059

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.81

PhyloP100

0.81

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.21

REVEL

Benign

0.12

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.026

Polyphen

0.99

Vest4

0.44

MutPred

0.23

Loss of phosphorylation at S464 (P = 0.001)

MVP

0.28

MPC

3.1

ClinPred

0.79

GERP RS

4.3

Varity_R

0.22

gMVP

0.45

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.46

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.46

Position offset: -7

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