13-43881104-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153218.4(LACC1):c.119A>C(p.Lys40Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LACC1 NM_153218.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19245625).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LACC1	NM_153218.4	c.119A>C	p.Lys40Thr	missense_variant	2/7	ENST00000325686.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LACC1	ENST00000325686.7	c.119A>C	p.Lys40Thr	missense_variant	2/7	1	NM_153218.4	P1
LACC1	ENST00000441843.5	c.119A>C	p.Lys40Thr	missense_variant	2/7	5		P1
LACC1	ENST00000425906.1	c.119A>C	p.Lys40Thr	missense_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2022

The c.119A>C (p.K40T) alteration is located in exon 2 (coding exon 1) of the LACC1 gene. This alteration results from a A to C substitution at nucleotide position 119, causing the lysine (K) at amino acid position 40 to be replaced by a threonine (T). 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	0.10
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.015	T;.;T
Eigen	Benign	-0.059
Eigen_PC	Benign	-0.015
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.77	T;T;.
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;.;M
MutationTaster	Benign	0.92	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.71	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.50	P;.;P
Vest4		0.46
MutPred		0.47		Loss of methylation at K40 (P = 0.0022);Loss of methylation at K40 (P = 0.0022);Loss of methylation at K40 (P = 0.0022);
MVP		0.59
MPC		0.58
ClinPred		0.62	D
GERP RS		3.3
Varity_R		0.098
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1955003344; hg19: chr13-44455240;