chr16-66805925-A-G

Position:

• chr16-66805925-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003905.4(NAE1):​c.1432T>C​(p.Tyr478His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NAE1 NM_003905.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.65

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAE1	NM_003905.4	c.1432T>C	p.Tyr478His	missense_variant	18/20	ENST00000290810.8	NP_003896.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAE1	ENST00000290810.8	c.1432T>C	p.Tyr478His	missense_variant	18/20	1	NM_003905.4	ENSP00000290810.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2024

The c.1432T>C (p.Y478H) alteration is located in exon 18 (coding exon 18) of the NAE1 gene. This alteration results from a T to C substitution at nucleotide position 1432, causing the tyrosine (Y) at amino acid position 478 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.084	T;.;T;.;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.58	D;D;D;D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	2.0	.;.;M;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.0	.;D;D;.;D;D
REVEL	Benign	0.24
Sift	Benign	0.081	.;T;T;.;T;T
Sift4G	Benign	0.20	T;T;T;D;T;T
Polyphen		1.0	.;.;D;.;.;.
Vest4		0.83, 0.83, 0.84, 0.86
MutPred		0.60		.;.;Loss of phosphorylation at Y478 (P = 0.0217);.;.;.;
MVP		0.63
MPC		0.37
ClinPred		0.86	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.67
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-66839828;