Genetic Variant NM_001172439.2:c.754C>T (chr12-47713386-G-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_001172439.2(ENDOU):c.754C>T(p.Arg252Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000447 in 1,612,044 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

ENDOU
NM_001172439.2 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.70

Publications

2 publications found

Variant links:

Genes affected

ENDOU (HGNC:14369): (endonuclease, poly(U) specific) This gene encodes a protein with endoribonuclease activity that binds polyuridine-enriched single-stranded RNA. This gene was initially characterized based on its high expression in placenta but was mischaracterized as a serine protease. In mouse, this gene promotes tolerance to self-antigens by regulating B cell activation-induced cell death (AICD). The protein may be useful as a tumor marker. Multiple alternatively spliced transcript variants encoding distinct protein isoforms have been found for this gene. [provided by RefSeq, Jul 2020]

ENDOU links:

RPAP3-DT (HGNC:55477): (RPAP3 divergent transcript)

RPAP3-DT links:

Genome browser will be placed here

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_001172439.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ENDOU	NM_001172439.2	MANE Select	c.754C>T	p.Arg252Cys	missense splice_region	Exon 7 of 10	NP_001165910.1	P21128-1
ENDOU	NM_006025.4		c.631C>T	p.Arg211Cys	missense splice_region	Exon 6 of 9	NP_006016.1	P21128-2
ENDOU	NM_001172440.2		c.565C>T	p.Arg189Cys	missense splice_region	Exon 5 of 8	NP_001165911.1	P21128-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ENDOU	ENST00000422538.8	TSL:1 MANE Select	c.754C>T	p.Arg252Cys	missense splice_region	Exon 7 of 10	ENSP00000397679.3	P21128-1
ENDOU	ENST00000229003.7	TSL:1	c.631C>T	p.Arg211Cys	missense splice_region	Exon 6 of 9	ENSP00000229003.3	P21128-2
ENDOU	ENST00000545824.2	TSL:2	c.565C>T	p.Arg189Cys	missense splice_region	Exon 5 of 8	ENSP00000445004.2	P21128-3

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152176

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000796

AC:

AN:

251350

AF XY:

0.0000883

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000445

AC:

AN:

1459750

Hom.:

Cov.:

AF XY:

0.0000441

AC XY:

AN XY:

726316

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33428

American (AMR)

AF:

0.000112

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.0000936

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000459

AC:

AN:

1110098

Other (OTH)

AF:

0.0000331

AC:

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41556

American (AMR)

AF:

0.0000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000988

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000296

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

Benign

0.12

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.053

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.54

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

PhyloP100

1.7

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.3

REVEL

Benign

0.15

Sift

Benign

0.17

Sift4G

Benign

0.18

Polyphen

1.0

Vest4

0.74

MVP

0.31

MPC

0.72

ClinPred

0.31

GERP RS

4.7

Varity_R

0.095

gMVP

0.66

Mutation Taster

=83/17

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over