17-35132441-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018096.5(NLE1):​c.1454G>A​(p.Arg485Lys) 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. 15/21 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

NLE1
NM_018096.5 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.38
Variant links:
Genes affected
NLE1 (HGNC:19889): (notchless homolog 1) Predicted to be involved in Notch signaling pathway and ribosomal large subunit assembly. Predicted to act upstream of or within several processes, including chordate embryonic development; hematopoietic stem cell homeostasis; and regulation of signal transduction. Located in nucleolus and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

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=0.110432744).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NLE1NM_018096.5 linkc.1454G>A p.Arg485Lys missense_variant Exon 13 of 13 ENST00000442241.9 NP_060566.2 Q9NVX2-1
NLE1NM_001014445.2 linkc.578G>A p.Arg193Lys missense_variant Exon 12 of 12 NP_001014445.1 Q9NVX2-2
NLE1XM_017024777.2 linkc.578G>A p.Arg193Lys missense_variant Exon 11 of 11 XP_016880266.1 Q9NVX2-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NLE1ENST00000442241.9 linkc.1454G>A p.Arg485Lys missense_variant Exon 13 of 13 1 NM_018096.5 ENSP00000413572.3 Q9NVX2-1
NLE1ENST00000586869.5 linkc.578G>A p.Arg193Lys missense_variant Exon 12 of 12 1 ENSP00000466588.1 Q9NVX2-2
NLE1ENST00000360831.9 linkc.1328G>A p.Arg443Lys missense_variant Exon 12 of 12 5 ENSP00000354075.5 A0A0A0MRH0
NLE1ENST00000588019.1 linkc.908G>A p.Arg303Lys missense_variant Exon 8 of 8 5 ENSP00000466764.1 K7EN33

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 09, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1454G>A (p.R485K) alteration is located in exon 13 (coding exon 13) of the NLE1 gene. This alteration results from a G to A substitution at nucleotide position 1454, causing the arginine (R) at amino acid position 485 to be replaced by a lysine (K). 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
0.12
BayesDel_addAF
Benign
-0.053
T
BayesDel_noAF
Benign
-0.31
CADD
Benign
22
DANN
Benign
0.73
DEOGEN2
Benign
0.099
.;T;T
Eigen
Benign
-0.19
Eigen_PC
Benign
-0.0041
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.82
T;T;T
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.11
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.99
.;L;.
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
-0.20
.;N;.
REVEL
Benign
0.18
Sift
Benign
0.99
.;T;.
Sift4G
Benign
0.98
T;T;T
Polyphen
0.0
.;B;.
Vest4
0.25
MutPred
0.43
.;Gain of methylation at R485 (P = 0.0043);.;
MVP
0.59
MPC
0.32
ClinPred
0.25
T
GERP RS
5.0
Varity_R
0.069
gMVP
0.71

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: chr17-33459460; API