9-135523918-G-T

Variant names:

• chr9-135523918-G-T
• rs146328087
• NM_002297.4:c.331G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002297.4(LCN1):​c.331G>T​(p.Val111Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V111M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: LCN1 NM_002297.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.823
• Publications: 0 publications found

Genes affected

LCN1 (HGNC:6525): (lipocalin 1) This gene encodes a member of the lipocalin family of small secretory proteins. Lipocalins are extracellular transport proteins that bind to a variety of hydrophobic ligands. The encoded protein is the primary lipid binding protein in tears and is overproduced in response to multiple stimuli including infection and stress. The encoded protein may be a marker for chromosome aneuploidy as well as an autoantigen in Sjogren's syndrome. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and two pseudogenes of this gene are also located on the long arm of chromosome 9. [provided by RefSeq, Nov 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10954827).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002297.4. 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
	LCN1	NM_002297.4	MANE Select	c.331G>T	p.Val111Leu	missense	Exon 4 of 7	NP_002288.1	P31025
	LCN1	NM_001252618.2		c.331G>T	p.Val111Leu	missense	Exon 4 of 7	NP_001239547.1
	LCN1	NM_001252619.2		c.331G>T	p.Val111Leu	missense	Exon 4 of 7	NP_001239548.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCN1	ENST00000371781.4	TSL:1 MANE Select	c.331G>T	p.Val111Leu	missense	Exon 4 of 7	ENSP00000360846.3	P31025
	LCN1	ENST00000263598.6	TSL:1	c.331G>T	p.Val111Leu	missense	Exon 4 of 7	ENSP00000263598.2	P31025

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251400 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461814 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	14
DANN	Benign	0.88
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.82
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.042
Sift	Benign	0.096	T
Sift4G	Benign	0.074	T
Polyphen		0.059	B
Vest4		0.36
MutPred		0.57		Loss of methylation at K112 (P = 0.0426)
MVP		0.32
MPC		0.16
ClinPred		0.048	T
GERP RS		0.19
Varity_R		0.42
gMVP		0.45
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs146328087; hg19: chr9-138415764;