Genetic Variant NM_006589.3:c.1580G>A (chr1-155248303-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_006589.3(ENTREP3):c.1580G>A(p.Gly527Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000055 in 1,455,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. G527V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ENTREP3
NM_006589.3 missense, splice_region

Scores

Splicing: ADA: 0.9955

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.77

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENTREP3	NM_006589.3 link	c.1580G>A	p.Gly527Glu	missense_variant, splice_region_variant	Exon 11 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.1580G>A	p.Gly527Glu	missense_variant, splice_region_variant	Exon 11 of 12	1	NM_006589.3	ENSP00000354958.2		P81408-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000550

AC:

AN:

1455158

Hom.:

Cov.:

AF XY:

0.00000415

AC XY:

AN XY:

722892

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33294

American (AMR)

AF:

0.00

AC:

AN:

44346

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25752

East Asian (EAS)

AF:

0.00

AC:

AN:

39578

South Asian (SAS)

AF:

0.00

AC:

AN:

85780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53180

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00000722

AC:

AN:

1107412

Other (OTH)

AF:

0.00

AC:

AN:

60072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

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

Uncertain

0.35

BayesDel_addAF

Uncertain

0.020

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0070

.;.;T;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.76

M_CAP

Benign

0.0046

MetaRNN

Benign

0.23

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.97

.;.;L;.

PhyloP100

1.8

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.33

N;N;N;N

REVEL

Benign

0.14

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Benign

0.087

T;T;T;T

Polyphen

1.0

D;.;D;.

Vest4

0.51

MutPred

0.30

.;.;Gain of helix (P = 0.0078);.;

MVP

0.37

MPC

0.52

ClinPred

0.78

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.17

gMVP

0.48

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.77

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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NM_006589.3:c.1580G>A

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