Genetic Variant LCN9:p.Thr135Lys (chr9-135665341-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001393661.1(LCN9):c.404C>A(p.Thr135Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LCN9
NM_001393661.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.134

Variant links:

Genes affected

LCN9 (HGNC:17442): (lipocalin 9) Members of the lipocalin family, such as LCN9, have a common structure consisting of an 8-stranded antiparallel beta-barrel that forms a cup-shaped ligand-binding pocket or calyx. Lipocalins generally bind small hydrophobic ligands and transport them to specific cells (Suzuki et al., 2004 [PubMed 15363845]).[supplied by OMIM, Aug 2009]

LCN9 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17800495).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCN9	NM_001393661.1 link	c.404C>A	p.Thr135Lys	missense_variant	Exon 4 of 6	ENST00000619315.2	NP_001380590.1
LCN9	NR_171893.1 link	n.417C>A		non_coding_transcript_exon_variant	Exon 4 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LCN9	ENST00000619315.2 link	c.404C>A	p.Thr135Lys	missense_variant	Exon 4 of 6	1	NM_001393661.1	ENSP00000482296.2	A0A087WZ21
LCN9	ENST00000277526.8 link	n.404C>A		non_coding_transcript_exon_variant	Exon 4 of 6	5		ENSP00000277526.4	Q8WX39
LCN9	ENST00000430290.6 link	n.390C>A		non_coding_transcript_exon_variant	Exon 4 of 6	5
LCN9	ENST00000554343.1 link	n.120C>A		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1447614

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718574

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:

0.00

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

Sep 01, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.404C>A (p.T135K) alteration is located in exon 4 (coding exon 4) of the LCN9 gene. This alteration results from a C to A substitution at nucleotide position 404, causing the threonine (T) at amino acid position 135 to be replaced by a lysine (K). 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

Uncertain

0.51

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.0096

.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.47

T;T

M_CAP

Benign

0.0028

MetaRNN

Benign

0.18

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.55

.;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.5

.;N

REVEL

Benign

0.051

Sift

Benign

0.063

.;T

Sift4G

Uncertain

0.013

D;D

Polyphen

0.42

.;B

Vest4

0.39

MutPred

0.64

Gain of ubiquitination at T135 (P = 0.0276);Gain of ubiquitination at T135 (P = 0.0276);

MVP

0.048

MPC

0.12

ClinPred

0.30

GERP RS

-0.67

Varity_R

0.14

gMVP

0.55

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

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