chr9-135521522-A-T

Variant names:

• chr9-135521522-A-T
• NM_002297.4:c.25A>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002297.4(LCN1):​c.25A>T​(p.Ser9Cys) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LCN1 NM_002297.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.417

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

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=0.27300555).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCN1	NM_002297.4	c.25A>T	p.Ser9Cys	missense_variant	Exon 1 of 7	ENST00000371781.4	NP_002288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LCN1	ENST00000371781.4	c.25A>T	p.Ser9Cys	missense_variant	Exon 1 of 7	1	NM_002297.4	ENSP00000360846.3
LCN1	ENST00000263598.6	c.25A>T	p.Ser9Cys	missense_variant	Exon 1 of 7	1		ENSP00000263598.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.25A>T (p.S9C) alteration is located in exon 1 (coding exon 1) of the LCN1 gene. This alteration results from a A to T substitution at nucleotide position 25, causing the serine (S) at amino acid position 9 to be replaced by a cysteine (C). 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	0.076
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.057	T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0037	N
LIST_S2	Benign	0.42	.;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.11
Sift	Benign	0.056	T;T
Sift4G	Benign	0.086	T;T
Polyphen		0.86	P;P
Vest4		0.30
MutPred		0.63		Gain of catalytic residue at L10 (P = 0.0192);Gain of catalytic residue at L10 (P = 0.0192);
MVP		0.29
MPC		0.39
ClinPred		0.62	D
GERP RS		-1.9
Varity_R		0.078
gMVP		0.68

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.

Other links and lift over

hg19: chr9-138413368;