rs730880295

Variant names:

• chr13-43883879-T-C
• rs730880295
• NM_153218.4:c.850T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 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
• Publications: 24 publications found

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]

LACC1 Gene-Disease associations (from GenCC):

• juvenile arthritis due to defect in LACC1

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000281883 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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 VariationId is 180673.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153218.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LACC1	NM_153218.4	MANE Select	c.850T>C	p.Cys284Arg	missense	Exon 4 of 7	NP_694950.2
	LACC1	NM_001128303.2		c.850T>C	p.Cys284Arg	missense	Exon 4 of 7	NP_001121775.1
	LACC1	NM_001350638.2		c.850T>C	p.Cys284Arg	missense	Exon 5 of 8	NP_001337567.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LACC1	ENST00000325686.7	TSL:1 MANE Select	c.850T>C	p.Cys284Arg	missense	Exon 4 of 7	ENSP00000317619.5
	ENSG00000281883	ENST00000627615.1	TSL:5	n.79T>C		non_coding_transcript_exon	Exon 1 of 13	ENSP00000486083.1
	LACC1	ENST00000441843.5	TSL:5	c.850T>C	p.Cys284Arg	missense	Exon 4 of 7	ENSP00000391747.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	1	-	Juvenile arthritis due to defect in LACC1 (4)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		6.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.92		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
Mutation Taster		=12/88	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs730880295; hg19: chr13-44458015;