Genetic Variant ENTREP2:p.Arg524His (chr15-29123388-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015307.2(ENTREP2):c.1571G>A(p.Arg524His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,546,044 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: 𝑓 0.0000066 ( 0 hom., cov: 35)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ENTREP2
NM_015307.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.317

Publications

0 publications found

Variant links:

Genes affected

ENTREP2 (HGNC:29075): (endosomal transmembrane epsin interactor 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENTREP2 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03509143).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENTREP2	NM_015307.2 link	c.1571G>A	p.Arg524His	missense_variant	Exon 11 of 11	ENST00000261275.5	NP_056122.1	O60320-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENTREP2	ENST00000261275.5 link	c.1571G>A	p.Arg524His	missense_variant	Exon 11 of 11	5	NM_015307.2	ENSP00000261275.4		O60320-1
ENTREP2	ENST00000560021.1 link	n.1307G>A		non_coding_transcript_exon_variant	Exon 8 of 8	1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000128

AC:

AN:

156454

AF XY:

0.00

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:

0.0000165

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000115

AC:

AN:

1393802

Hom.:

Cov.:

AF XY:

0.00000874

AC XY:

AN XY:

686170

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31506

American (AMR)

AF:

0.00

AC:

AN:

35600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25118

East Asian (EAS)

AF:

0.00

AC:

AN:

35526

South Asian (SAS)

AF:

0.0000379

AC:

AN:

79128

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48758

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.0000112

AC:

AN:

1074724

Other (OTH)

AF:

0.0000173

AC:

AN:

57760

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41476

American (AMR)

AF:

0.0000654

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 10, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1571G>A (p.R524H) alteration is located in exon 11 (coding exon 11) of the FAM189A1 gene. This alteration results from a G to A substitution at nucleotide position 1571, causing the arginine (R) at amino acid position 524 to be replaced by a histidine (H). 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

0.060

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.7

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0035

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.42

M_CAP

Benign

0.0044

MetaRNN

Benign

0.035

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

0.32

PrimateAI

Benign

0.19

PROVEAN

Benign

-1.5

REVEL

Benign

0.045

Sift

Benign

0.14

Sift4G

Benign

0.13

Polyphen

0.0080

Vest4

0.062

MutPred

0.20

Gain of disorder (P = 0.2263);

MVP

0.014

ClinPred

0.075

GERP RS

-7.8

Varity_R

0.024

gMVP

0.054

Mutation Taster

=98/2

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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chr15-29123388-C-T

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