Genetic Variant NM_016231.5:c.208T>A (chr17-28043081-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_016231.5(NLK):c.208T>A (p.Ser70Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000704 (AC=1) in the gnomAD database across 1,420,218 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000917. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

NLK
NM_016231.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.29

Publications

0 publications found

Variant links:

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]

NLK links:

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new If you want to explore the variant's impact on the transcript NM_016231.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 points.

PM2

Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000917 — very rare for unknown gene (threshold 0.001) — PM2 moderate.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_016231.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NLK	NM_016231.5	MANE Select	c.208T>A	p.Ser70Thr	missense	Exon 1 of 11	NP_057315.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NLK	ENST00000407008.8	TSL:1 MANE Select	c.208T>A	p.Ser70Thr	missense	Exon 1 of 11	ENSP00000384625.3	Q9UBE8
NLK	ENST00000955373.1		c.208T>A	p.Ser70Thr	missense	Exon 2 of 12	ENSP00000625432.1	Q9UBE8
NLK	ENST00000923558.1		c.208T>A	p.Ser70Thr	missense	Exon 1 of 11	ENSP00000593617.1	A0ACI8T789

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.04e-7

AC:

AN:

1420218

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

703042

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32332

American (AMR)

AF:

0.00

AC:

AN:

36790

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25536

East Asian (EAS)

AF:

0.00

AC:

AN:

37260

South Asian (SAS)

AF:

0.00

AC:

AN:

82796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

9.17e-7

AC:

AN:

1090384

Other (OTH)

AF:

0.00

AC:

AN:

58836

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.30

Eigen

Benign

-0.10

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.72

M_CAP

Benign

0.032

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.0

PhyloP100

5.3

PrimateAI

Uncertain

0.65

PROVEAN

Benign

0.0

REVEL

Benign

0.092

Sift

Benign

0.17

Sift4G

Benign

0.59

PromoterAI

-0.045

Neutral

(source)

Varity_R

0.12

gMVP

0.35

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over