16-66809049-C-T

Variant names:

• chr16-66809049-C-T
• rs751561000
• NM_003905.4:c.1177G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_003905.4(NAE1):​c.1177G>A​(p.Val393Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,612,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. V393L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NAE1 NM_003905.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.61
• Publications: 0 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 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24223372).

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.1177G>A	p.Val393Ile	missense	Exon 16 of 20	NP_003896.1	Q13564-1
	NAE1	NM_001286500.2		c.1186G>A	p.Val396Ile	missense	Exon 16 of 20	NP_001273429.1	Q13564-4
	NAE1	NM_001018159.2		c.1159G>A	p.Val387Ile	missense	Exon 17 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.1177G>A	p.Val393Ile	missense	Exon 16 of 20	ENSP00000290810.3	Q13564-1
	NAE1	ENST00000934206.1		c.1210G>A	p.Val404Ile	missense	Exon 16 of 20	ENSP00000604265.1
	NAE1	ENST00000359087.8	TSL:2	c.1186G>A	p.Val396Ile	missense	Exon 16 of 20	ENSP00000351990.4	Q13564-4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460108 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 726366

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.0000898 AC: 4 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110968

Other (OTH) AF: 0.0000166 AC: 1 AN: 60308

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74290

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.043	T
Eigen	Benign	-0.085
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.6
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.15
Sift	Benign	0.57	T
Sift4G	Benign	0.66	T
Polyphen		0.49	P
Vest4		0.67
MutPred		0.43		Gain of catalytic residue at V393 (P = 0.0684)
MVP		0.48
MPC		0.17
ClinPred		0.87	D
GERP RS		5.1
Varity_R		0.16
gMVP		0.38

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

Other links and lift over

dbSNP: rs751561000; hg19: chr16-66842952;