17-35133436-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018096.5. 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
	NLE1	NM_018096.5	MANE Select	c.1277G>A	p.Ser426Asn	missense	Exon 11 of 13	NP_060566.2	Q9NVX2-1
	NLE1	NM_001014445.2		c.401G>A	p.Ser134Asn	missense	Exon 10 of 12	NP_001014445.1	Q9NVX2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLE1	ENST00000442241.9	TSL:1 MANE Select	c.1277G>A	p.Ser426Asn	missense	Exon 11 of 13	ENSP00000413572.3	Q9NVX2-1
	NLE1	ENST00000586869.5	TSL:1	c.401G>A	p.Ser134Asn	missense	Exon 10 of 12	ENSP00000466588.1	Q9NVX2-2
	NLE1	ENST00000932057.1		c.1157G>A	p.Ser386Asn	missense	Exon 11 of 13	ENSP00000602116.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.51	N
PhyloP100		7.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.25
Sift	Benign	0.066	T
Sift4G	Benign	0.18	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

Other links and lift over

dbSNP: rs2091889431; hg19: chr17-33460455;