Genetic Variant NAE1:c.1237+98T>A (chr16-66808891-A-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_003905.4(NAE1):c.1237+98T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.474 in 739,290 control chromosomes in the GnomAD database, including 85,709 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.51 ( 20848 hom., cov: 33)

Exomes 𝑓: 0.46 ( 64861 hom. )

Consequence

NAE1
NM_003905.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.584

Publications

8 publications found

Variant links:

Genes affected

NAE1 (HGNC:621): (NEDD8 activating enzyme E1 subunit 1) The protein encoded by this gene binds to the beta-amyloid precursor protein. Beta-amyloid precursor protein is a cell surface protein with signal-transducing properties, and it is thought to play a role in the pathogenesis of Alzheimer's disease. In addition, the encoded protein can form a heterodimer with UBE1C and bind and activate NEDD8, a ubiquitin-like protein. This protein is required for cell cycle progression through the S/M checkpoint. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

NAE1 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

NAE1 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 (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAE1	NM_003905.4 link	c.1237+98T>A		intron_variant	Intron 16 of 19	ENST00000290810.8	NP_003896.1	Q13564-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAE1	ENST00000290810.8 link	c.1237+98T>A		intron_variant	Intron 16 of 19	1	NM_003905.4	ENSP00000290810.3		Q13564-1

Frequencies

GnomAD3 genomes

AF:

0.514

AC:

77990

AN:

151860

Hom.:

20811

Cov.:

show subpopulations

Gnomad AFR

AF:

0.640

Gnomad AMI

AF:

0.432

Gnomad AMR

AF:

0.531

Gnomad ASJ

AF:

0.563

Gnomad EAS

AF:

0.633

Gnomad SAS

AF:

0.581

Gnomad FIN

AF:

0.428

Gnomad MID

AF:

0.516

Gnomad NFE

AF:

0.431

Gnomad OTH

AF:

0.503

GnomAD4 exome

AF:

0.464

AC:

272301

AN:

587312

Hom.:

64861

Cov.:

AF XY:

0.467

AC XY:

141233

AN XY:

302174

show subpopulations

African (AFR)

AF:

0.634

AC:

8237

AN:

12988

American (AMR)

AF:

0.544

AC:

7020

AN:

12898

Ashkenazi Jewish (ASJ)

AF:

0.562

AC:

8226

AN:

14646

East Asian (EAS)

AF:

0.632

AC:

17677

AN:

27976

South Asian (SAS)

AF:

0.579

AC:

19905

AN:

34386

European-Finnish (FIN)

AF:

0.432

AC:

17958

AN:

41534

Middle Eastern (MID)

AF:

0.545

AC:

1354

AN:

2484

European-Non Finnish (NFE)

AF:

0.433

AC:

177860

AN:

411126

Other (OTH)

AF:

0.480

AC:

14064

AN:

29274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

7009

14018

21027

28036

35045

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.514

AC:

78086

AN:

151978

Hom.:

20848

Cov.:

AF XY:

0.516

AC XY:

38318

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.640

AC:

26517

AN:

41426

American (AMR)

AF:

0.531

AC:

8113

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.563

AC:

1954

AN:

3468

East Asian (EAS)

AF:

0.633

AC:

3278

AN:

5182

South Asian (SAS)

AF:

0.580

AC:

2803

AN:

4830

European-Finnish (FIN)

AF:

0.428

AC:

4500

AN:

10524

Middle Eastern (MID)

AF:

0.524

AC:

153

AN:

292

European-Non Finnish (NFE)

AF:

0.431

AC:

29303

AN:

67962

Other (OTH)

AF:

0.509

AC:

1071

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1888

3777

5665

7554

9442

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.465

Hom.:

2129

Bravo

AF:

0.525

Asia WGS

AF:

0.625

AC:

2160

AN:

3458

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.97

(source)

DANN

Benign

0.66

PhyloP100

-0.58

PromoterAI

-0.0018

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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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chr16-66808891-A-T

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