chr18-49565473-C-T

Variant names:

• chr18-49565473-C-T
• rs2084594724
• NM_006033.4:c.254C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006033.4(LIPG):​c.254C>T​(p.Thr85Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LIPG NM_006033.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.90

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPG	NM_006033.4	c.254C>T	p.Thr85Ile	missense_variant	Exon 2 of 10	ENST00000261292.9	NP_006024.1
LIPG	NM_001308006.2	c.254C>T	p.Thr85Ile	missense_variant	Exon 2 of 9		NP_001294935.1
LIPG	XM_047437944.1	c.362C>T	p.Thr121Ile	missense_variant	Exon 2 of 5		XP_047293900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIPG	ENST00000261292.9	c.254C>T	p.Thr85Ile	missense_variant	Exon 2 of 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

Jan 24, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.254C>T (p.T85I) alteration is located in exon 2 (coding exon 2) of the LIPG gene. This alteration results from a C to T substitution at nucleotide position 254, causing the threonine (T) at amino acid position 85 to be replaced by an isoleucine (I). 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	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.;D;D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;T;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.5	.;.;M;.;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.6	.;.;D;D;.
REVEL	Pathogenic	0.89
Sift	Benign	0.031	.;.;D;D;.
Sift4G	Uncertain	0.013	D;D;T;T;D
Polyphen		0.98, 0.99	.;.;D;D;D
Vest4		0.92
MutPred		0.85		.;.;Gain of ubiquitination at K84 (P = 0.0543);Gain of ubiquitination at K84 (P = 0.0543);Gain of ubiquitination at K84 (P = 0.0543);
MVP		0.99
MPC		1.1
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.64
gMVP		0.78

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: rs2084594724; hg19: chr18-47091843;