Genetic Variant LPIN1:p.Ile577Phe (chr2-11791929-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001349206.2(LPIN1):c.1729A>T(p.Ile577Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I577V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

LPIN1
NM_001349206.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.99

Publications

6 publications found

Variant links:

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]

LPIN1 Gene-Disease associations (from GenCC):

myoglobinuria, acute recurrent, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
hereditary recurrent myoglobinuria
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LPIN1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349206.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LPIN1	NM_001349206.2	MANE Select	c.1729A>T	p.Ile577Phe	missense	Exon 13 of 21	NP_001336135.1	Q14693-3
LPIN1	NM_001261428.3		c.1876A>T	p.Ile626Phe	missense	Exon 14 of 22	NP_001248357.1	Q14693-7
LPIN1	NM_001349207.2		c.1819A>T	p.Ile607Phe	missense	Exon 13 of 21	NP_001336136.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LPIN1	ENST00000674199.1	MANE Select	c.1729A>T	p.Ile577Phe	missense	Exon 13 of 21	ENSP00000501331.1	Q14693-3
LPIN1	ENST00000256720.6	TSL:1	c.1621A>T	p.Ile541Phe	missense	Exon 12 of 20	ENSP00000256720.2	Q14693-1
LPIN1	ENST00000404113.6	TSL:1	n.1214A>T		non_coding_transcript_exon	Exon 8 of 16

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

Eigen

Benign

0.16

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.069

MetaRNN

Uncertain

0.43

MetaSVM

Uncertain

0.087

MutationAssessor

Uncertain

2.7

PhyloP100

4.0

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.59

REVEL

Uncertain

0.45

Sift

Benign

0.034

Sift4G

Benign

0.064

Polyphen

0.21

Vest4

0.72

MutPred

0.58

Loss of MoRF binding (P = 0.1069)

MVP

0.86

MPC

0.54

ClinPred

0.84

GERP RS

4.5

Varity_R

0.089

gMVP

0.66

Mutation Taster

=69/31

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over