rs4669781

chr2-11802956-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.19

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=0.0020134747).
• 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/exons	MANE	UniProt
LPIN1	NM_001349206.2	c.1936C>T	p.Pro646Ser	missense_variant	15/21	ENST00000674199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPIN1	ENST00000674199.1	c.1936C>T	p.Pro646Ser	missense_variant	15/21		NM_001349206.2	P4

Frequencies

GnomAD3 genomes AF: 0.0375 AC: 5708 AN: 152230 Hom.: 150 Cov.: 32

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

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.: 32 AF XY: 0.0497 AC XY: 36099 AN XY: 726798

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.: 32 AF XY: 0.0368 AC XY: 2742 AN XY: 74496

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: 53

ESP6500EA AF: 0.0535 AC: 460

ExAC AF: 0.0454 AC: 5515

Asia WGS AF: 0.0220 AC: 76 AN: 3478

EpiCase AF: 0.0484

EpiControl AF: 0.0455

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 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:1

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. -

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	0.082
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	15
Dann	Uncertain	0.98
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.86	D;D;D;D;D
MetaRNN	Benign	0.0020	T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	0.88	D;D;D;D;D;D
PrimateAI	Benign	0.30	T
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	T
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

Other links and lift over

dbSNP: rs4669781; hg19: chr2-11943082; COSMIC: COSV56765296; COSMIC: COSV56765296;