2-30533194-A-C

Position:

• chr2-30533194-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001002257.3(LCLAT1):​c.244A>C​(p.Ile82Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LCLAT1 NM_001002257.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.19

Genes affected

LCLAT1 (HGNC:26756): (lysocardiolipin acyltransferase 1) Enables 1-acylglycerol-3-phosphate O-acyltransferase activity. Predicted to be involved in phosphatidylinositol acyl-chain remodeling. Located in cytosol and endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LCLAT1	NM_001002257.3	c.244A>C	p.Ile82Leu	missense_variant	3/6	ENST00000379509.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LCLAT1	ENST00000379509.8	c.244A>C	p.Ile82Leu	missense_variant	3/6	1	NM_001002257.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461702 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727180

Gnomad4 AFR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2022

The c.358A>C (p.I120L) alteration is located in exon 4 (coding exon 3) of the LCLAT1 gene. This alteration results from a A to C substitution at nucleotide position 358, causing the isoleucine (I) at amino acid position 120 to be replaced by a leucine (L). 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	0.20
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.44	T;.;.;.;.;.;D;.;.;.
Eigen	Benign	0.048
Eigen_PC	Benign	0.081
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	1.8	.;.;.;L;.;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.69
Sift	Benign	0.10	T;T;T;T;D;D;T;D;T;D
Sift4G	Pathogenic	0.0	D;D;D;T;D;D;D;D;D;D
Polyphen		0.51, 0.78	.;.;.;P;.;.;P;.;.;.
Vest4		0.76, 0.75, 0.77
MutPred		0.71		.;.;.;Loss of MoRF binding (P = 0.148);.;.;Loss of MoRF binding (P = 0.148);.;Loss of MoRF binding (P = 0.148);.;
MVP		0.81
MPC		0.56
ClinPred		0.92	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.89

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: rs1010412528; hg19: chr2-30756060;