rs4669781

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001349206.2(LPIN1):c.1936C>T(p.Pro646Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0482 in 1,613,376 control chromosomes in the GnomAD database, including 2,118 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 149 hom., cov: 32)

Exomes 𝑓: 0.049 ( 1969 hom. )

Consequence

LPIN1
NM_001349206.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.19

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020134747).

BP6

Variant 2-11802956-C-T is Benign according to our data. Variant chr2-11802956-C-T is described in ClinVar as [Benign]. Clinvar id is 262587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPIN1	NM_001349206.2 link	c.1936C>T	p.Pro646Ser	missense_variant	Exon 15 of 21	ENST00000674199.1	NP_001336135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPIN1	ENST00000674199.1 link	c.1936C>T	p.Pro646Ser	missense_variant	Exon 15 of 21		NM_001349206.2	ENSP00000501331.1		Q14693-3

Frequencies

GnomAD3 genomes

AF:

0.0375

AC:

5708

AN:

152230

Hom.:

150

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00996

Gnomad AMI

AF:

0.0659

Gnomad AMR

AF:

0.0551

Gnomad ASJ

AF:

0.0404

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0631

Gnomad FIN

AF:

0.0289

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0524

Gnomad OTH

AF:

0.0325

GnomAD3 exomes

AF:

0.0448

AC:

11264

AN:

251296

Hom.:

321

AF XY:

0.0461

AC XY:

6255

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.00843

Gnomad AMR exome

AF:

0.0562

Gnomad ASJ exome

AF:

0.0368

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0620

Gnomad FIN exome

AF:

0.0279

Gnomad NFE exome

AF:

0.0532

Gnomad OTH exome

AF:

0.0437

GnomAD4 exome

AF:

0.0493

AC:

72046

AN:

1461028

Hom.:

1969

Cov.:

AF XY:

0.0497

AC XY:

36099

AN XY:

726798

show subpopulations

Gnomad4 AFR exome

AF:

0.00669

Gnomad4 AMR exome

AF:

0.0561

Gnomad4 ASJ exome

AF:

0.0372

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0632

Gnomad4 FIN exome

AF:

0.0328

Gnomad4 NFE exome

AF:

0.0524

Gnomad4 OTH exome

AF:

0.0443

GnomAD4 genome

AF:

0.0375

AC:

5707

AN:

152348

Hom.:

149

Cov.:

AF XY:

0.0368

AC XY:

2742

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00993

Gnomad4 AMR

AF:

0.0551

Gnomad4 ASJ

AF:

0.0404

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0629

Gnomad4 FIN

AF:

0.0289

Gnomad4 NFE

AF:

0.0524

Gnomad4 OTH

AF:

0.0317

Alfa

AF:

0.0471

Hom.:

303

Bravo

AF:

0.0360

TwinsUK

AF:

0.0475

AC:

176

ALSPAC

AF:

0.0558

AC:

215

ESP6500AA

AF:

0.0120

AC:

ESP6500EA

AF:

0.0535

AC:

460

ExAC

AF:

0.0454

AC:

5515

Asia WGS

AF:

0.0220

AC:

AN:

3478

EpiCase

AF:

0.0484

EpiControl

AF:

0.0455

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Jul 10, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myoglobinuria, acute recurrent, autosomal recessive

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.092

.;.;.;T;T

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.31

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.86

D;D;D;D;D

MetaRNN

Benign

0.0020

T;T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.90

.;.;.;L;.

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.84

N;N;.;N;N

REVEL

Benign

0.27

Sift

Benign

0.20

T;T;.;T;T

Sift4G

Benign

0.29

T;T;T;T;T

Polyphen

0.0020

.;.;.;B;.

Vest4

0.051

MPC

0.18

ClinPred

0.0068

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.31

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over