17-28172607-C-T

Variant names:

• chr17-28172607-C-T
• rs1435116420
• NM_016231.5:c.1138C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016231.5(NLK):​c.1138C>T​(p.Pro380Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000713 in 1,402,876 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P380A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: NLK NM_016231.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.39
• Publications: 0 publications found

Genes affected

NLK (HGNC:29858): (nemo like kinase) Enables ubiquitin protein ligase binding activity. Involved in protein stabilization and transforming growth factor beta receptor signaling pathway. Predicted to be located in cytosol and nucleoplasm. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000301334 (HGNC:):

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_016231.5. 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
	NLK	NM_016231.5	MANE Select	c.1138C>T	p.Pro380Ser	missense	Exon 7 of 11	NP_057315.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLK	ENST00000407008.8	TSL:1 MANE Select	c.1138C>T	p.Pro380Ser	missense	Exon 7 of 11	ENSP00000384625.3	Q9UBE8
	NLK	ENST00000955373.1		c.1138C>T	p.Pro380Ser	missense	Exon 8 of 12	ENSP00000625432.1
	NLK	ENST00000923558.1		c.1138C>T	p.Pro380Ser	missense	Exon 7 of 11	ENSP00000593617.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1402876 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 696366

African (AFR) AF: 0.00 AC: 0 AN: 30814

American (AMR) AF: 0.00 AC: 0 AN: 37328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24762

East Asian (EAS) AF: 0.00 AC: 0 AN: 35936

South Asian (SAS) AF: 0.00 AC: 0 AN: 76154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5624

European-Non Finnish (NFE) AF: 9.24e-7 AC: 1 AN: 1082424

Other (OTH) AF: 0.00 AC: 0 AN: 57730

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	0.0054	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.81	L
PhyloP100		4.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.20
Sift	Benign	0.069	T
Sift4G	Uncertain	0.057	T
Polyphen		0.80	P
Vest4		0.47
MutPred		0.49		Loss of loop (P = 0.0512)
MVP		0.44
MPC		1.7
ClinPred		0.96	D
GERP RS		6.0
Varity_R		0.29
gMVP		0.72
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1435116420; hg19: chr17-26499633;