Genetic Variant NLK:p.Pro36Ser (chr17-28042979-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_016231.5(NLK):c.106C>T(p.Pro36Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000027 in 1,557,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

NLK
NM_016231.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.19

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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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.034779996).

BS2

High AC in GnomAd4 at 25 AD gene.

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.106C>T	p.Pro36Ser	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.106C>T	p.Pro36Ser	missense	Exon 1 of 11	ENSP00000384625.3	Q9UBE8
NLK	ENST00000955373.1		c.106C>T	p.Pro36Ser	missense	Exon 2 of 12	ENSP00000625432.1
NLK	ENST00000923558.1		c.106C>T	p.Pro36Ser	missense	Exon 1 of 11	ENSP00000593617.1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.0000354

AC:

AN:

169344

AF XY:

0.0000225

show subpopulations

Gnomad AFR exome

AF:

0.000521

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000210

GnomAD4 exome

AF:

0.0000121

AC:

AN:

1405144

Hom.:

Cov.:

AF XY:

0.0000144

AC XY:

AN XY:

693536

show subpopulations

African (AFR)

AF:

0.000534

AC:

AN:

31836

American (AMR)

AF:

0.00

AC:

AN:

36158

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25276

East Asian (EAS)

AF:

0.00

AC:

AN:

36370

South Asian (SAS)

AF:

0.00

AC:

AN:

79774

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49786

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081870

Other (OTH)

AF:

0.00

AC:

AN:

58368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000164

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.000530

AC:

AN:

41532

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68006

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.000147

ESP6500AA

AF:

0.000685

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000356

AC:

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

0.10

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.27

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.69

M_CAP

Benign

0.024

MetaRNN

Benign

0.035

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

PhyloP100

3.2

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.16

REVEL

Benign

0.20

Sift

Benign

0.40

Sift4G

Benign

0.23

Polyphen

0.0

Vest4

0.21

MVP

0.45

MPC

1.7

ClinPred

0.11

GERP RS

4.4

PromoterAI

0.0036

Neutral

(source)

Varity_R

0.066

gMVP

0.39

Mutation Taster

=78/22

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over