dbSNP rs3743477: AEN:p.Pro15Leu (chr15-88626253-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_022767.4(AEN):c.44C>T(p.Pro15Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0543 in 1,611,698 control chromosomes in the GnomAD database, including 2,977 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.072 ( 505 hom., cov: 33)

Exomes 𝑓: 0.052 ( 2472 hom. )

Consequence

AEN
NM_022767.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.792

Publications

7 publications found

Variant links:

Genes affected

AEN (HGNC:25722): (apoptosis enhancing nuclease) Enables exonuclease activity. Involved in intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator and response to ionizing radiation. Located in nuclear membrane; nucleolus; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

AEN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014880002).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AEN	NM_022767.4 link	c.44C>T	p.Pro15Leu	missense_variant	Exon 2 of 4	ENST00000332810.4	NP_073604.3	Q8WTP8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AEN	ENST00000332810.4 link	c.44C>T	p.Pro15Leu	missense_variant	Exon 2 of 4	1	NM_022767.4	ENSP00000331944.3		Q8WTP8-1

Frequencies

GnomAD3 genomes

AF:

0.0719

AC:

10952

AN:

152228

Hom.:

499

Cov.:

show subpopulations

Gnomad AFR

AF:

0.123

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.0489

Gnomad ASJ

AF:

0.0616

Gnomad EAS

AF:

0.000961

Gnomad SAS

AF:

0.0928

Gnomad FIN

AF:

0.0664

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.0518

Gnomad OTH

AF:

0.0640

GnomAD2 exomes

AF:

0.0582

AC:

14440

AN:

247938

AF XY:

0.0603

show subpopulations

Gnomad AFR exome

AF:

0.124

Gnomad AMR exome

AF:

0.0319

Gnomad ASJ exome

AF:

0.0636

Gnomad EAS exome

AF:

0.000656

Gnomad FIN exome

AF:

0.0758

Gnomad NFE exome

AF:

0.0515

Gnomad OTH exome

AF:

0.0651

GnomAD4 exome

AF:

0.0524

AC:

76512

AN:

1459352

Hom.:

2472

Cov.:

AF XY:

0.0542

AC XY:

39331

AN XY:

725796

show subpopulations

African (AFR)

AF:

0.125

AC:

4184

AN:

33440

American (AMR)

AF:

0.0342

AC:

1525

AN:

44592

Ashkenazi Jewish (ASJ)

AF:

0.0623

AC:

1617

AN:

25970

East Asian (EAS)

AF:

0.00131

AC:

AN:

39646

South Asian (SAS)

AF:

0.0986

AC:

8485

AN:

86016

European-Finnish (FIN)

AF:

0.0751

AC:

3961

AN:

52778

Middle Eastern (MID)

AF:

0.0866

AC:

496

AN:

5730

European-Non Finnish (NFE)

AF:

0.0474

AC:

52682

AN:

1110904

Other (OTH)

AF:

0.0582

AC:

3510

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

4467

8935

13402

17870

22337

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2012

4024

6036

8048

10060

<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:

0.0721

AC:

10977

AN:

152346

Hom.:

505

Cov.:

AF XY:

0.0727

AC XY:

5419

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.123

AC:

5127

AN:

41568

American (AMR)

AF:

0.0489

AC:

748

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0616

AC:

214

AN:

3472

East Asian (EAS)

AF:

0.000963

AC:

AN:

5190

South Asian (SAS)

AF:

0.0914

AC:

442

AN:

4834

European-Finnish (FIN)

AF:

0.0664

AC:

705

AN:

10620

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0518

AC:

3527

AN:

68038

Other (OTH)

AF:

0.0681

AC:

144

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

507

1014

1522

2029

2536

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

248

372

496

620

<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:

0.0537

Hom.:

678

Bravo

AF:

0.0704

TwinsUK

AF:

0.0518

AC:

192

ALSPAC

AF:

0.0451

AC:

174

ESP6500AA

AF:

0.116

AC:

509

ESP6500EA

AF:

0.0512

AC:

440

ExAC

AF:

0.0603

AC:

7319

Asia WGS

AF:

0.0640

AC:

222

AN:

3478

EpiCase

AF:

0.0509

EpiControl

AF:

0.0522

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.021

T;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.70

T;T

MetaRNN

Benign

0.0015

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.98

L;.

PhyloP100

0.79

PrimateAI

Benign

0.39

PROVEAN

Benign

0.26

N;N

REVEL

Benign

0.047

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

0.0010

B;.

Vest4

0.067

MPC

0.084

ClinPred

0.0054

GERP RS

2.3

Varity_R

0.079

gMVP

0.38

Mutation Taster

=100/0

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over