2-11787112-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001349206.2(LPIN1):c.1588G>A(p.Val530Met) variant causes a missense change. The variant allele was found at a frequency of 0.0174 in 1,613,934 control chromosomes in the GnomAD database, including 342 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 34 hom., cov: 32)

Exomes 𝑓: 0.017 ( 308 hom. )

Consequence

LPIN1
NM_001349206.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.37

Publications

16 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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
hereditary recurrent myoglobinuria
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LPIN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00783357).

BP6

Variant 2-11787112-G-A is Benign according to our data. Variant chr2-11787112-G-A is described in ClinVar as Benign. ClinVar VariationId is 262583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0167 (2548/152302) while in subpopulation NFE AF = 0.024 (1635/68022). AF 95% confidence interval is 0.0231. There are 34 homozygotes in GnomAd4. There are 1227 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 34 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPIN1	NM_001349206.2 link	c.1588G>A	p.Val530Met	missense_variant	Exon 11 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.1588G>A	p.Val530Met	missense_variant	Exon 11 of 21		NM_001349206.2	ENSP00000501331.1		Q14693-3

Frequencies

GnomAD3 genomes

AF:

0.0167

AC:

2549

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00384

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0144

Gnomad ASJ

AF:

0.0268

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.0357

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0240

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.0164

AC:

4122

AN:

251410

AF XY:

0.0165

show subpopulations

Gnomad AFR exome

AF:

0.00326

Gnomad AMR exome

AF:

0.0146

Gnomad ASJ exome

AF:

0.0294

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0317

Gnomad NFE exome

AF:

0.0209

Gnomad OTH exome

AF:

0.0174

GnomAD4 exome

AF:

0.0175

AC:

25561

AN:

1461632

Hom.:

308

Cov.:

AF XY:

0.0174

AC XY:

12657

AN XY:

727144

show subpopulations

African (AFR)

AF:

0.00293

AC:

AN:

33478

American (AMR)

AF:

0.0142

AC:

637

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0283

AC:

740

AN:

26132

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39698

South Asian (SAS)

AF:

0.00330

AC:

285

AN:

86254

European-Finnish (FIN)

AF:

0.0326

AC:

1742

AN:

53414

Middle Eastern (MID)

AF:

0.0184

AC:

106

AN:

5768

European-Non Finnish (NFE)

AF:

0.0188

AC:

20944

AN:

1111776

Other (OTH)

AF:

0.0167

AC:

1006

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

1222

2444

3667

4889

6111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

698

1396

2094

2792

3490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0167

AC:

2548

AN:

152302

Hom.:

Cov.:

AF XY:

0.0165

AC XY:

1227

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00382

AC:

159

AN:

41570

American (AMR)

AF:

0.0144

AC:

221

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0268

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00310

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0357

AC:

379

AN:

10606

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0240

AC:

1635

AN:

68022

Other (OTH)

AF:

0.0194

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

126

252

377

503

629

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0195

Hom.:

122

Bravo

AF:

0.0135

TwinsUK

AF:

0.0162

AC:

ALSPAC

AF:

0.0205

AC:

ESP6500AA

AF:

0.00499

AC:

ESP6500EA

AF:

0.0221

AC:

190

ExAC

AF:

0.0157

AC:

1903

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0219

EpiControl

AF:

0.0219

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Nov 16, 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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Myoglobinuria, acute recurrent, autosomal recessive

Benign:2

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. -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.16

.;.;.;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

D;D;D;D

MetaRNN

Benign

0.0078

T;T;T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Pathogenic

2.9

.;.;.;M

PhyloP100

4.4

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.5

N;N;.;N

REVEL

Benign

0.19

Sift

Uncertain

0.012

D;D;.;D

Sift4G

Uncertain

0.032

D;D;D;D

Polyphen

0.24

.;.;.;B

Vest4

0.21

MPC

0.51

ClinPred

0.035

GERP RS

5.6

PromoterAI

-0.022

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.38

Mutation Taster

=298/2

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over