Genetic Variant ENTREP3:p.Pro472Leu (chr1-155250371-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006589.3(ENTREP3):c.1415C>T(p.Pro472Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000055 in 1,545,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

ENTREP3
NM_006589.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.50

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17391777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENTREP3	NM_006589.3 link	c.1415C>T	p.Pro472Leu	missense_variant	Exon 9 of 12	ENST00000361361.7	NP_006580.2	P81408-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENTREP3	ENST00000361361.7 link	c.1415C>T	p.Pro472Leu	missense_variant	Exon 9 of 12	1	NM_006589.3	ENSP00000354958.2		P81408-1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.0000627

AC:

AN:

143460

AF XY:

0.0000262

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000206

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000773

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000524

AC:

AN:

1393094

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

687228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31096

American (AMR)

AF:

0.000283

AC:

AN:

35326

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24926

East Asian (EAS)

AF:

0.00

AC:

AN:

35328

South Asian (SAS)

AF:

0.0000127

AC:

AN:

78898

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4100

European-Non Finnish (NFE)

AF:

0.0000520

AC:

AN:

1077392

Other (OTH)

AF:

0.000104

AC:

AN:

57622

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.000458

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68022

Other (OTH)

AF:

0.000957

AC:

AN:

2090

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

Alfa

AF:

0.0000853

Hom.:

Bravo

AF:

0.000249

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 28, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1415C>T (p.P472L) alteration is located in exon 9 (coding exon 9) of the FAM189B gene. This alteration results from a C to T substitution at nucleotide position 1415, causing the proline (P) at amino acid position 472 to be replaced by a leucine (L). 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

0.13

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.025

.;.;T

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Benign

0.62

M_CAP

Benign

0.018

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

0.55

.;.;N

PhyloP100

3.5

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.099

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.011

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.29

MVP

0.40

MPC

2.8

ClinPred

0.23

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.34

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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chr1-155250371-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over