Genetic Variant NM_016231.5:c.793A>G (chr17-28163584-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_016231.5(NLK):c.793A>G(p.Ile265Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 1,609,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

NLK
NM_016231.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.86

Publications

4 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:

ENSG00000301334 (HGNC:):

ENSG00000301334 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19936833).

BS2

High AC in GnomAd4 at 21 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.793A>G	p.Ile265Val	missense	Exon 5 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.793A>G	p.Ile265Val	missense	Exon 5 of 11	ENSP00000384625.3	Q9UBE8
NLK	ENST00000955373.1		c.793A>G	p.Ile265Val	missense	Exon 6 of 12	ENSP00000625432.1
NLK	ENST00000923558.1		c.793A>G	p.Ile265Val	missense	Exon 5 of 11	ENSP00000593617.1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000230

AC:

AN:

247532

AF XY:

0.000262

show subpopulations

Gnomad AFR exome

AF:

0.0000625

Gnomad AMR exome

AF:

0.000176

Gnomad ASJ exome

AF:

0.00261

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000170

Gnomad OTH exome

AF:

0.000828

GnomAD4 exome

AF:

0.000167

AC:

244

AN:

1457454

Hom.:

Cov.:

AF XY:

0.000181

AC XY:

131

AN XY:

724892

show subpopulations

African (AFR)

AF:

0.0000599

AC:

AN:

33408

American (AMR)

AF:

0.000157

AC:

AN:

44530

Ashkenazi Jewish (ASJ)

AF:

0.00338

AC:

AN:

26026

East Asian (EAS)

AF:

0.00

AC:

AN:

39588

South Asian (SAS)

AF:

0.0000351

AC:

AN:

85530

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53302

Middle Eastern (MID)

AF:

0.00174

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000848

AC:

AN:

1109096

Other (OTH)

AF:

0.000664

AC:

AN:

60222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

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:

0.000138

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41572

American (AMR)

AF:

0.000196

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.000335

Hom.:

Bravo

AF:

0.000189

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000115

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

0.32

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.62

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.029

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.68

PhyloP100

8.9

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.98

REVEL

Uncertain

0.36

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Polyphen

0.97

Vest4

0.62

MVP

0.59

MPC

1.9

ClinPred

0.095

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.58

Mutation Taster

=31/69

disease causing

(source)

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

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