rs11538448

Positions:

• chr2-11771635-C-G
• chr2-11771635-C-T

Variant summary

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

The NM_001349206.2(LPIN1):​c.552C>G​(p.Ile184Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,451,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I184I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: LPIN1 NM_001349206.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.748

Genes affected

LPIN1 (HGNC:13345): (lipin 1) This gene encodes a magnesium-ion-dependent phosphatidic acid phosphohydrolase enzyme that catalyzes the penultimate step in triglyceride synthesis including the dephosphorylation of phosphatidic acid to yield diacylglycerol. Expression of this gene is required for adipocyte differentiation and it also functions as a nuclear transcriptional coactivator with some peroxisome proliferator-activated receptors to modulate expression of other genes involved in lipid metabolism. Mutations in this gene are associated with metabolic syndrome, type 2 diabetes, acute recurrent rhabdomyolysis, and autosomal recessive acute recurrent myoglobinuria (ARARM). This gene is also a candidate for several human lipodystrophy syndromes. [provided by RefSeq, Mar 2017]

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=0.07737288).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LPIN1	NM_001349206.2	c.552C>G	p.Ile184Met	missense_variant	4/21	ENST00000674199.1	NP_001336135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LPIN1	ENST00000674199.1	c.552C>G	p.Ile184Met	missense_variant	4/21		NM_001349206.2	ENSP00000501331	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000413 AC: 6 AN: 1451628 Hom.: 0 Cov.: 33 AF XY: 0.00000416 AC XY: 3 AN XY: 720908

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: 0.00000452

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.0023	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	0.19
DANN	Benign	0.94
DEOGEN2	Benign	0.088	.;.;.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.83	T;T;T;T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.077	T;T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.4	.;.;.;.;L
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.74	N;N;.;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.28	T;T;.;T;T
Sift4G	Benign	0.28	T;T;T;T;T
Polyphen		0.075	.;.;.;.;B
Vest4		0.26
MutPred		0.20		.;.;.;.;Gain of catalytic residue at I184 (P = 0.1089);
MVP		0.52
MPC		0.19
ClinPred		0.33	T
GERP RS		-9.1
Varity_R		0.066
gMVP		0.20

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: rs11538448; hg19: chr2-11911761;