16-66810743-G-T

Position:

• chr16-66810743-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003905.4(NAE1):​c.1064C>A​(p.Ala355Asp) variant causes a missense 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NAE1 NM_003905.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.17

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13780668).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAE1	NM_003905.4	c.1064C>A	p.Ala355Asp	missense_variant	14/20	ENST00000290810.8	NP_003896.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAE1	ENST00000290810.8	c.1064C>A	p.Ala355Asp	missense_variant	14/20	1	NM_003905.4	ENSP00000290810.3
NAE1	ENST00000359087.8	c.1073C>A	p.Ala358Asp	missense_variant	14/20	2		ENSP00000351990.4
NAE1	ENST00000379463.6	c.1046C>A	p.Ala349Asp	missense_variant	15/21	2		ENSP00000368776.2
NAE1	ENST00000394074.6	c.797C>A	p.Ala266Asp	missense_variant	13/19	5		ENSP00000377637.2

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

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 06, 2024

Variant summary: NAE1 c.1064C>A (p.Ala355Asp) results in a non-conservative amino acid change located in the THIF-type NAD/FAD binding fold domain (IPR000594) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251434 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1064C>A in individuals affected with Neurodevelopmental Disorder With Dysmorphic Facies And Ischiopubic Hypoplasia and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.040	.;T;.;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.86	D;D;D;T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	.;L;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.11	N;N;N;N
REVEL	Benign	0.049
Sift	Benign	0.73	T;T;T;T
Sift4G	Benign	0.62	T;T;T;T
Polyphen		0.0	.;B;.;.
Vest4		0.34
MutPred		0.37		.;Loss of MoRF binding (P = 0.056);.;.;
MVP		0.51
MPC		0.32
ClinPred		0.61	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.67

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: chr16-66844646;