17-35133436-C-T

Variant names:

• chr17-35133436-C-T
• rs2091889431
• NM_018096.5:c.1277G>A

Variant summary

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

The NM_018096.5(NLE1):​c.1277G>A​(p.Ser426Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NLE1 NM_018096.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.19

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLE1	NM_018096.5	c.1277G>A	p.Ser426Asn	missense_variant	Exon 11 of 13	ENST00000442241.9	NP_060566.2
NLE1	NM_001014445.2	c.401G>A	p.Ser134Asn	missense_variant	Exon 10 of 12		NP_001014445.1
NLE1	XM_017024777.2	c.401G>A	p.Ser134Asn	missense_variant	Exon 9 of 11		XP_016880266.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLE1	ENST00000442241.9	c.1277G>A	p.Ser426Asn	missense_variant	Exon 11 of 13	1	NM_018096.5	ENSP00000413572.3
NLE1	ENST00000586869.5	c.401G>A	p.Ser134Asn	missense_variant	Exon 10 of 12	1		ENSP00000466588.1
NLE1	ENST00000360831.9	c.1151G>A	p.Ser384Asn	missense_variant	Exon 10 of 12	5		ENSP00000354075.5
NLE1	ENST00000588019.1	c.731G>A	p.Ser244Asn	missense_variant	Exon 6 of 8	5		ENSP00000466764.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461792 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1277G>A (p.S426N) 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 1277, causing the serine (S) at amino acid position 426 to be replaced by an asparagine (N). 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	Pathogenic	0.63
BayesDel_addAF	Benign	-0.0041	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	.;T;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.51	.;N;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.9	.;D;.
REVEL	Benign	0.25
Sift	Benign	0.066	.;T;.
Sift4G	Benign	0.18	T;T;T
Polyphen		1.0	.;D;.
Vest4		0.65
MutPred		0.63		.;Loss of disorder (P = 0.0773);.;
MVP		0.66
MPC		0.80
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.63
gMVP		0.60

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

LitVar

Other links and lift over

dbSNP: rs2091889431; hg19: chr17-33460455;