Genetic Variant ENTREP3:p.His655Arg (chr1-155247825-T-C) – 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_006589.3(ENTREP3):c.1964A>G(p.His655Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000754 in 1,326,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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: 7.5e-7 ( 0 hom. )

Consequence

ENTREP3
NM_006589.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.698

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1711348).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENTREP3	NM_006589.3 link	c.1964A>G	p.His655Arg	missense_variant	Exon 12 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.1964A>G	p.His655Arg	missense_variant	Exon 12 of 12	1	NM_006589.3	ENSP00000354958.2		P81408-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.54e-7

AC:

AN:

1326498

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

646634

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29362

American (AMR)

AF:

0.00

AC:

AN:

22970

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19616

East Asian (EAS)

AF:

0.00

AC:

AN:

36328

South Asian (SAS)

AF:

0.00

AC:

AN:

66156

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4562

European-Non Finnish (NFE)

AF:

9.56e-7

AC:

AN:

1046444

Other (OTH)

AF:

0.00

AC:

AN:

54690

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 03, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1964A>G (p.H655R) alteration is located in exon 12 (coding exon 12) of the FAM189B gene. This alteration results from a A to G substitution at nucleotide position 1964, causing the histidine (H) at amino acid position 655 to be replaced by an arginine (R). 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

0.077

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.019

.;.;T

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.84

M_CAP

Benign

0.0059

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

.;.;N

PhyloP100

0.70

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.0

N;N;N

REVEL

Benign

0.067

Sift

Uncertain

0.0070

D;D;D

Sift4G

Benign

0.73

T;T;T

Polyphen

0.069

B;.;B

Vest4

0.18

MutPred

0.28

.;.;Gain of MoRF binding (P = 0.0307);

MVP

0.45

MPC

0.11

ClinPred

0.83

GERP RS

4.5

Varity_R

0.15

gMVP

0.55

Mutation Taster

=92/8

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over