17-35132441-C-T

Variant names:

• chr17-35132441-C-T
• NM_018096.5:c.1454G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.38

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]

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=0.110432744).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLE1	NM_018096.5	c.1454G>A	p.Arg485Lys	missense_variant	Exon 13 of 13	ENST00000442241.9	NP_060566.2
NLE1	NM_001014445.2	c.578G>A	p.Arg193Lys	missense_variant	Exon 12 of 12		NP_001014445.1
NLE1	XM_017024777.2	c.578G>A	p.Arg193Lys	missense_variant	Exon 11 of 11		XP_016880266.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLE1	ENST00000442241.9	c.1454G>A	p.Arg485Lys	missense_variant	Exon 13 of 13	1	NM_018096.5	ENSP00000413572.3
NLE1	ENST00000586869.5	c.578G>A	p.Arg193Lys	missense_variant	Exon 12 of 12	1		ENSP00000466588.1
NLE1	ENST00000360831.9	c.1328G>A	p.Arg443Lys	missense_variant	Exon 12 of 12	5		ENSP00000354075.5
NLE1	ENST00000588019.1	c.908G>A	p.Arg303Lys	missense_variant	Exon 8 of 8	5		ENSP00000466764.1

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

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;