chr13-43883789-A-G

Variant names:

• chr13-43883789-A-G
• rs3764147
• NM_153218.4:c.760A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153218.4(LACC1):​c.760A>G​(p.Ile254Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,609,972 control chromosomes in the GnomAD database, including 48,467 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I254M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.27 (5714 hom., cov: 32)
  • Exomes 𝑓: 0.24 (42753 hom.)
• Consequence: LACC1 NM_153218.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 2.74
• Publications: 167 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043236315).
• BP6: Variant 13-43883789-A-G is Benign according to our data. Variant chr13-43883789-A-G is described in ClinVar as Benign. ClinVar VariationId is 1300105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

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.760A>G	p.Ile254Val	missense	Exon 4 of 7	NP_694950.2
	LACC1	NM_001128303.2		c.760A>G	p.Ile254Val	missense	Exon 4 of 7	NP_001121775.1
	LACC1	NM_001350638.2		c.760A>G	p.Ile254Val	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.760A>G	p.Ile254Val	missense	Exon 4 of 7	ENSP00000317619.5
	LACC1	ENST00000441843.5	TSL:5	c.760A>G	p.Ile254Val	missense	Exon 4 of 7	ENSP00000391747.1
	ENSG00000281883	ENST00000627615.1	TSL:5	n.-12A>G		upstream_gene	N/A	ENSP00000486083.1

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40822 AN: 151930 Hom.: 5706 Cov.: 32

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.400

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.259

GnomAD2 exomes AF: 0.277 AC: 69444 AN: 250572 AF XY: 0.274

Gnomad AFR exome AF: 0.310

Gnomad AMR exome AF: 0.395

Gnomad ASJ exome AF: 0.401

Gnomad EAS exome AF: 0.311

Gnomad FIN exome AF: 0.210

Gnomad NFE exome AF: 0.231

Gnomad OTH exome AF: 0.263

GnomAD4 exome AF: 0.236 AC: 343712 AN: 1457924 Hom.: 42753 Cov.: 31 AF XY: 0.238 AC XY: 172651 AN XY: 725398

African (AFR) AF: 0.311 AC: 10372 AN: 33356

American (AMR) AF: 0.383 AC: 17014 AN: 44476

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 10392 AN: 26042

East Asian (EAS) AF: 0.320 AC: 12678 AN: 39638

South Asian (SAS) AF: 0.296 AC: 25460 AN: 85908

European-Finnish (FIN) AF: 0.205 AC: 10931 AN: 53332

Middle Eastern (MID) AF: 0.281 AC: 1619 AN: 5756

European-Non Finnish (NFE) AF: 0.217 AC: 240702 AN: 1109180

Other (OTH) AF: 0.241 AC: 14544 AN: 60236

GnomAD4 genome AF: 0.269 AC: 40850 AN: 152048 Hom.: 5714 Cov.: 32 AF XY: 0.271 AC XY: 20149 AN XY: 74328

African (AFR) AF: 0.309 AC: 12803 AN: 41458

American (AMR) AF: 0.326 AC: 4974 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 1387 AN: 3468

East Asian (EAS) AF: 0.318 AC: 1642 AN: 5164

South Asian (SAS) AF: 0.297 AC: 1431 AN: 4816

European-Finnish (FIN) AF: 0.207 AC: 2191 AN: 10574

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.231 AC: 15678 AN: 67968

Other (OTH) AF: 0.258 AC: 546 AN: 2114

Alfa AF: 0.248 Hom.: 24622

Bravo AF: 0.279

TwinsUK AF: 0.214 AC: 792

ALSPAC AF: 0.221 AC: 851

ESP6500AA AF: 0.294 AC: 1297

ESP6500EA AF: 0.230 AC: 1981

ExAC AF: 0.270 AC: 32755

Asia WGS AF: 0.257 AC: 889 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 45% of patients studied by a panel of primary immunodeficiencies. Number of patients: 40. Only high quality variants are reported.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Juvenile arthritis due to defect in LACC1 Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leprosy, susceptibility to, 1 Other:1

Jun 10, 2022

Centro Dermatológico Federico Lleras Acosta, Hospital Universitario Centro Dermatológico Federico Lleras Acosta

Significance: Uncertain risk allele

Review Status: no assertion criteria provided

Collection Method: case-control

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.80
DANN	Benign	0.84
DEOGEN2	Benign	0.0048	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.5	N
PhyloP100		2.7
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.43	N
REVEL	Benign	0.036
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.023
MPC		0.28
ClinPred		0.00037	T
GERP RS		1.9
Varity_R		0.034
gMVP		0.65
Mutation Taster		=98/2	polymorphism (auto)

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: rs3764147; hg19: chr13-44457925; COSMIC: COSV57828643; COSMIC: COSV57828643;