rs33997857

chr2-11787112-G-Achr2-11787112-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.37

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 Benign. Variant got -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 id is 262583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-11787112-G-A is described in Lovd as [Benign]. Variant chr2-11787112-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPIN1	NM_001349206.2	c.1588G>A	p.Val530Met	missense_variant	11/21	ENST00000674199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPIN1	ENST00000674199.1	c.1588G>A	p.Val530Met	missense_variant	11/21		NM_001349206.2	P4

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 2549 AN: 152184 Hom.: 34 Cov.: 32

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

GnomAD3 exomes AF: 0.0164 AC: 4122 AN: 251410 Hom.: 45 AF XY: 0.0165 AC XY: 2247 AN XY: 135900

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 SAS exome AF: 0.00310

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.: 31 AF XY: 0.0174 AC XY: 12657 AN XY: 727144

Gnomad4 AFR exome AF: 0.00293

Gnomad4 AMR exome AF: 0.0142

Gnomad4 ASJ exome AF: 0.0283

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00330

Gnomad4 FIN exome AF: 0.0326

Gnomad4 NFE exome AF: 0.0188

Gnomad4 OTH exome AF: 0.0167

GnomAD4 genome AF: 0.0167 AC: 2548 AN: 152302 Hom.: 34 Cov.: 32 AF XY: 0.0165 AC XY: 1227 AN XY: 74466

Gnomad4 AFR AF: 0.00382

Gnomad4 AMR AF: 0.0144

Gnomad4 ASJ AF: 0.0268

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00310

Gnomad4 FIN AF: 0.0357

Gnomad4 NFE AF: 0.0240

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.0203 Hom.: 61

Bravo AF: 0.0135

TwinsUK AF: 0.0162 AC: 60

ALSPAC AF: 0.0205 AC: 79

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.0221 AC: 190

ExAC AF: 0.0157 AC: 1903

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0219

EpiControl AF: 0.0219

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2017	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. -

Myoglobinuria, acute recurrent, autosomal recessive Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	23
Dann	Pathogenic	1.0
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D;D;D
MetaRNN	Benign	0.0078	T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationTaster	Benign	1.0	D;N;N;N;N;N
PrimateAI	Uncertain	0.54	T
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	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.38

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: rs33997857; hg19: chr2-11927238;