18-49565335-A-C

Position:

• chr18-49565335-A-C

Variant summary

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

The NM_006033.4(LIPG):​c.116A>C​(p.Lys39Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K39Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LIPG NM_006033.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.618

Genes affected

LIPG (HGNC:6623): (lipase G, endothelial type) The protein encoded by this gene has substantial phospholipase activity and may be involved in lipoprotein metabolism and vascular biology. This protein is designated a member of the TG lipase family by its sequence and characteristic lid region which provides substrate specificity for enzymes of the TG lipase family. [provided by RefSeq, Jul 2008]

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=0.12716481).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIPG	NM_006033.4	c.116A>C	p.Lys39Thr	missense_variant	2/10	ENST00000261292.9	NP_006024.1
LIPG	NM_001308006.2	c.116A>C	p.Lys39Thr	missense_variant	2/9		NP_001294935.1
LIPG	XM_047437944.1	c.224A>C	p.Lys75Thr	missense_variant	2/5		XP_047293900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIPG	ENST00000261292.9	c.116A>C	p.Lys39Thr	missense_variant	2/10	1	NM_006033.4	ENSP00000261292.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Nov 29, 2023

The c.116A>C (p.K39T) alteration is located in exon 2 (coding exon 2) of the LIPG gene. This alteration results from a A to C substitution at nucleotide position 116, causing the lysine (K) at amino acid position 39 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	0.072
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	0.28
DANN	Benign	0.48
DEOGEN2	Benign	0.0050	T;T;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.67	T;T;T;T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.34	.;N;.;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.25	.;N;N;.
REVEL	Benign	0.23
Sift	Benign	0.48	.;T;T;.
Sift4G	Benign	0.36	T;T;T;T
Polyphen		0.0	.;B;B;B
Vest4		0.17
MutPred		0.52		.;Loss of methylation at K39 (P = 0.0032);Loss of methylation at K39 (P = 0.0032);Loss of methylation at K39 (P = 0.0032);
MVP		0.80
MPC		0.42
ClinPred		0.44	T
GERP RS		-4.9
Varity_R		0.062
gMVP		0.30

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: rs2084591631; hg19: chr18-47091705;