Genetic Variant NM_018096.5:c.1350G>A (chr17-35133363-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018096.5(NLE1):c.1350G>A(p.Met450Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M450T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NLE1
NM_018096.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.80

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]

NLE1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06573567).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLE1	NM_018096.5 link	c.1350G>A	p.Met450Ile	missense_variant	Exon 11 of 13	ENST00000442241.9	NP_060566.2	Q9NVX2-1
NLE1	NM_001014445.2 link	c.474G>A	p.Met158Ile	missense_variant	Exon 10 of 12		NP_001014445.1	Q9NVX2-2
NLE1	XM_017024777.2 link	c.474G>A	p.Met158Ile	missense_variant	Exon 9 of 11		XP_016880266.1	Q9NVX2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NLE1	ENST00000442241.9 link	c.1350G>A	p.Met450Ile	missense_variant	Exon 11 of 13	1	NM_018096.5	ENSP00000413572.3	Q9NVX2-1
NLE1	ENST00000586869.5 link	c.474G>A	p.Met158Ile	missense_variant	Exon 10 of 12	1		ENSP00000466588.1	Q9NVX2-2
NLE1	ENST00000360831.9 link	c.1224G>A	p.Met408Ile	missense_variant	Exon 10 of 12	5		ENSP00000354075.5	A0A0A0MRH0
NLE1	ENST00000588019.1 link	c.804G>A	p.Met268Ile	missense_variant	Exon 6 of 8	5		ENSP00000466764.1	K7EN33

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251444

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1350G>A (p.M450I) alteration is located in exon 11 (coding exon 11) of the NLE1 gene. This alteration results from a G to A substitution at nucleotide position 1350, causing the methionine (M) at amino acid position 450 to be replaced by an isoleucine (I). 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

-0.38

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.097

DANN

Benign

0.82

DEOGEN2

Benign

0.15

.;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.83

T;T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.066

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.39

.;N;.

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.93

.;N;.

REVEL

Benign

0.0030

Sift

Benign

0.52

.;T;.

Sift4G

Benign

0.45

T;T;T

Polyphen

0.0

.;B;.

Vest4

0.12

MutPred

0.31

.;Loss of catalytic residue at M450 (P = 0.0331);.;

MVP

0.67

MPC

0.35

ClinPred

0.028

GERP RS

-4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.034

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over