dbSNP rs363209: NAE1:c.402-4A>G (chr16-66821563-T-C) – 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_003905.4(NAE1):c.402-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NAE1
NM_003905.4 splice_region, intron

Scores

Splicing: ADA: 0.9717

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.479

Publications

1 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

NAE1 links:

Genome browser will be placed here

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, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003905.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NAE1	NM_003905.4	MANE Select	c.402-4A>G	splice_region intron	N/A	NP_003896.1	Q13564-1
NAE1	NM_001286500.2		c.411-4A>G	splice_region intron	N/A	NP_001273429.1	Q13564-4
NAE1	NM_001018159.2		c.384-4A>G	splice_region intron	N/A	NP_001018169.1	Q13564-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NAE1	ENST00000290810.8	TSL:1 MANE Select	c.402-4A>G	splice_region intron	N/A	ENSP00000290810.3	Q13564-1
NAE1	ENST00000567743.5	TSL:1	n.*220-4A>G	splice_region intron	N/A	ENSP00000455562.1	H3BQ16
NAE1	ENST00000934206.1		c.402-4A>G	splice_region intron	N/A	ENSP00000604265.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1403264

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

696774

African (AFR)

AF:

0.00

AC:

AN:

30212

American (AMR)

AF:

0.00

AC:

AN:

30138

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23348

East Asian (EAS)

AF:

0.00

AC:

AN:

38662

South Asian (SAS)

AF:

0.00

AC:

AN:

77204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5490

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090300

Other (OTH)

AF:

0.00

AC:

AN:

57666

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

(source)

DANN

Benign

0.66

PhyloP100

-0.48

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Pathogenic

0.83

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.98

Position offset: -1

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over