chr2-30640367-T-G

Position:

• chr2-30640367-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001002257.3(LCLAT1):​c.879T>G​(p.Ser293Arg) 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 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LCLAT1 NM_001002257.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.136

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054498613).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LCLAT1	NM_001002257.3	c.879T>G	p.Ser293Arg	missense_variant	6/6	ENST00000379509.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LCLAT1	ENST00000379509.8	c.879T>G	p.Ser293Arg	missense_variant	6/6	1	NM_001002257.3	P1
LCLAT1	ENST00000309052.8	c.993T>G	p.Ser331Arg	missense_variant	7/7	1
LCLAT1	ENST00000491680.6	n.1030T>G		non_coding_transcript_exon_variant	6/6	2
LCLAT1	ENST00000478015.5	c.*1026T>G		3_prime_UTR_variant, NMD_transcript_variant	8/8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727248

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.: 32

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

Mar 27, 2023

The c.993T>G (p.S331R) alteration is located in exon 7 (coding exon 6) of the LCLAT1 gene. This alteration results from a T to G substitution at nucleotide position 993, causing the serine (S) at amino acid position 331 to be replaced by an arginine (R). 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	0.19
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.76
DANN	Benign	0.64
DEOGEN2	Benign	0.086	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.054	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	.;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.15	N;N
REVEL	Benign	0.014
Sift	Benign	0.48	T;T
Sift4G	Benign	0.59	T;T
Polyphen		0.26	.;B
Vest4		0.15
MutPred		0.38		.;Gain of catalytic residue at S331 (P = 0.0687);
MVP		0.11
MPC		0.31
ClinPred		0.50	D
GERP RS		-5.3
Varity_R		0.024
gMVP		0.64

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: rs190394850; hg19: chr2-30863233;