16-66817004-A-T

Variant names:

• chr16-66817004-A-T
• rs201659718
• NM_003905.4:c.709T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_003905.4(NAE1):​c.709T>A​(p.Tyr237Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y237D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NAE1 NM_003905.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.13
• Publications: 1 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 3 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.091 (below the threshold of 3.09). Trascript score misZ: 1.0379 (below the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAE1	NM_003905.4	MANE Select	c.709T>A	p.Tyr237Asn	missense	Exon 10 of 20	NP_003896.1	Q13564-1
	NAE1	NM_001286500.2		c.718T>A	p.Tyr240Asn	missense	Exon 10 of 20	NP_001273429.1	Q13564-4
	NAE1	NM_001018159.2		c.691T>A	p.Tyr231Asn	missense	Exon 11 of 21	NP_001018169.1	Q13564-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAE1	ENST00000290810.8	TSL:1 MANE Select	c.709T>A	p.Tyr237Asn	missense	Exon 10 of 20	ENSP00000290810.3	Q13564-1
	NAE1	ENST00000567743.5	TSL:1	n.*923T>A		non_coding_transcript_exon	Exon 8 of 8	ENSP00000455562.1	H3BQ16
	NAE1	ENST00000567743.5	TSL:1	n.*923T>A		3_prime_UTR	Exon 8 of 8	ENSP00000455562.1	H3BQ16

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 238332 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.012	D
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.84
MutPred		0.34		Gain of helix (P = 0.0425)
MVP		0.75
MPC		0.61
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.78
gMVP		0.76

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

Other links and lift over

dbSNP: rs201659718; hg19: chr16-66850907;