13-43881097-A-G

Position:

• chr13-43881097-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_153218.4(LACC1):​c.112A>G​(p.Lys38Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00541 in 1,614,198 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K38R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0048 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (43 hom.)
• Consequence: LACC1 NM_153218.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.70

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053784847).
• BP6: Variant 13-43881097-A-G is Benign according to our data. Variant chr13-43881097-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 721083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-43881097-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00483 (736/152348) while in subpopulation SAS AF= 0.0058 (28/4830). AF 95% confidence interval is 0.00429. There are 6 homozygotes in gnomad4. There are 429 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LACC1	NM_153218.4	c.112A>G	p.Lys38Glu	missense_variant	2/7	ENST00000325686.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LACC1	ENST00000325686.7	c.112A>G	p.Lys38Glu	missense_variant	2/7	1	NM_153218.4	P1
LACC1	ENST00000441843.5	c.112A>G	p.Lys38Glu	missense_variant	2/7	5		P1
LACC1	ENST00000425906.1	c.112A>G	p.Lys38Glu	missense_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00484 AC: 737 AN: 152230 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.0297

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00472

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00612 AC: 1539 AN: 251446 Hom.: 13 AF XY: 0.00604 AC XY: 821 AN XY: 135894

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00399

Gnomad FIN exome AF: 0.0297

Gnomad NFE exome AF: 0.00585

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00547 AC: 7998 AN: 1461850 Hom.: 43 Cov.: 32 AF XY: 0.00545 AC XY: 3967 AN XY: 727224

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00184

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00413

Gnomad4 FIN exome AF: 0.0282

Gnomad4 NFE exome AF: 0.00517

Gnomad4 OTH exome AF: 0.00397

GnomAD4 genome AF: 0.00483 AC: 736 AN: 152348 Hom.: 6 Cov.: 32 AF XY: 0.00576 AC XY: 429 AN XY: 74506

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.0297

Gnomad4 NFE AF: 0.00472

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00428 Hom.: 4

Bravo AF: 0.00264

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00477 AC: 41

ExAC AF: 0.00580 AC: 704

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	LACC1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0075	T;.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.63	T;T;.
MetaRNN	Benign	0.0054	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.13	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.40	T;T;T
Sift4G	Benign	0.68	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.16
MVP		0.43
MPC		0.46
ClinPred		0.012	T
GERP RS		4.7
Varity_R		0.10
gMVP		0.28

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: rs34414396; hg19: chr13-44455233;