Genetic Variant NLK:p.Ala119Gly (chr17-28043229-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_016231.5(NLK):c.356C>G(p.Ala119Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,680 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: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NLK
NM_016231.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.61

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:

LOC102724517 (HGNC:):

LOC102724517 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2707435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLK	NM_016231.5 link	c.356C>G	p.Ala119Gly	missense_variant	Exon 1 of 11	ENST00000407008.8	NP_057315.3	Q9UBE8A0A024QZ12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NLK	ENST00000407008.8 link	c.356C>G	p.Ala119Gly	missense_variant	Exon 1 of 11	1	NM_016231.5	ENSP00000384625.3	Q9UBE8
NLK	ENST00000582037.2 link	c.356C>G	p.Ala119Gly	missense_variant	Exon 1 of 2	2		ENSP00000464656.1	J3QSE9
NLK	ENST00000496808.1 link	n.200C>G		non_coding_transcript_exon_variant	Exon 1 of 12	2		ENSP00000433117.1	H0YD75
NLK	ENST00000583517.1 link	n.185C>G		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461680

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.356C>G (p.A119G) alteration is located in exon 1 (coding exon 1) of the NLK gene. This alteration results from a C to G substitution at nucleotide position 356, causing the alanine (A) at amino acid position 119 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Uncertain

0.018

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

T;.

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.27

T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

0.55

N;.

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.93

N;.

REVEL

Benign

0.15

Sift

Benign

0.036

D;.

Sift4G

Benign

0.13

T;T

Polyphen

0.64

P;.

Vest4

0.41

MutPred

0.35

Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);

MVP

0.73

MPC

0.98

ClinPred

0.77

GERP RS

5.3

Varity_R

0.18

gMVP

0.45

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over