rs730880295

Positions:

• chr13-43883879-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_153218.4(LACC1):​c.850T>C​(p.Cys284Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LACC1 NM_153218.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 6.93

Genes affected

LACC1 (HGNC:26789): (laccase domain containing 1) This gene encodes an oxidoreductase that promotes fatty-acid oxidation, with concomitant inflammasome activation, mitochondrial and NADPH-oxidase-dependent reactive oxygen species production, and bactericidal activity of macrophages. The encoded protein forms a complex with fatty acid synthase on peroxisomes and is thought to be modulated by peroxisome proliferator-activated receptor signaling events. Naturally occurring mutations in this gene are associated with inflammatory bowel disease, Behcet's disease, leprosy, ulcerative colitis, early-onset Crohn's disease, and systemic juvenile idiopathic arthritis. [provided by RefSeq, Apr 2017]

ENSG00000281883 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity LACC1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 13-43883879-T-C is Pathogenic according to our data. Variant chr13-43883879-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180673.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LACC1	NM_153218.4	c.850T>C	p.Cys284Arg	missense_variant	4/7	ENST00000325686.7	NP_694950.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LACC1	ENST00000325686.7	c.850T>C	p.Cys284Arg	missense_variant	4/7	1	NM_153218.4	ENSP00000317619.5
ENSG00000281883	ENST00000627615.1	n.79T>C		non_coding_transcript_exon_variant	1/13	5		ENSP00000486083.1
LACC1	ENST00000441843.5	c.850T>C	p.Cys284Arg	missense_variant	4/7	5		ENSP00000391747.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Juvenile arthritis due to defect in LACC1 Pathogenic:3 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 10, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 09, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Pathogenic:1

Likely pathogenic, flagged submission

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Aug 21, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T;.
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;H
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-12	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.92		Loss of catalytic residue at C284 (P = 0.2769);Loss of catalytic residue at C284 (P = 0.2769);
MVP		0.92
MPC		1.5
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		1.0

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

LitVar

Other links and lift over

dbSNP: rs730880295; hg19: chr13-44458015;