2-11677686-G-C

Variant summary

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

The NM_001261428.3(LPIN1):c.39G>C(p.Glu13Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 1,535,318 control chromosomes in the GnomAD database, including 315,062 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (24959 hom., cov: 33)
  • Exomes 𝑓: 0.64 (290103 hom.)
• Consequence: LPIN1 NM_001261428.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.349

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=2.3455743E-6).
• BP6: Variant 2-11677686-G-C is Benign according to our data. Variant chr2-11677686-G-C is described in ClinVar as [Benign]. Clinvar id is 403044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPIN1	NM_001261428.3	c.39G>C	p.Glu13Asp	missense_variant	1/22
LPIN1	NM_001349207.2	c.39G>C	p.Glu13Asp	missense_variant	1/21
LPIN1	NM_001349208.2	c.39G>C	p.Glu13Asp	missense_variant	1/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPIN1	ENST00000449576.6	c.39G>C	p.Glu13Asp	missense_variant	1/22	2		A2

Frequencies

GnomAD3 genomes AF: 0.554 AC: 84307 AN: 152048 Hom.: 24969 Cov.: 33

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.808

Gnomad AMR AF: 0.610

Gnomad ASJ AF: 0.607

Gnomad EAS AF: 0.390

Gnomad SAS AF: 0.661

Gnomad FIN AF: 0.615

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.659

Gnomad OTH AF: 0.565

GnomAD3 exomes AF: 0.606 AC: 77797 AN: 128392 Hom.: 24214 AF XY: 0.613 AC XY: 43095 AN XY: 70310

Gnomad AFR exome AF: 0.341

Gnomad AMR exome AF: 0.626

Gnomad ASJ exome AF: 0.599

Gnomad EAS exome AF: 0.390

Gnomad SAS exome AF: 0.654

Gnomad FIN exome AF: 0.629

Gnomad NFE exome AF: 0.653

Gnomad OTH exome AF: 0.603

GnomAD4 exome AF: 0.644 AC: 890257 AN: 1383152 Hom.: 290103 Cov.: 51 AF XY: 0.645 AC XY: 440311 AN XY: 682504

Gnomad4 AFR exome AF: 0.330

Gnomad4 AMR exome AF: 0.615

Gnomad4 ASJ exome AF: 0.597

Gnomad4 EAS exome AF: 0.411

Gnomad4 SAS exome AF: 0.659

Gnomad4 FIN exome AF: 0.619

Gnomad4 NFE exome AF: 0.664

Gnomad4 OTH exome AF: 0.614

GnomAD4 genome AF: 0.554 AC: 84321 AN: 152166 Hom.: 24959 Cov.: 33 AF XY: 0.554 AC XY: 41180 AN XY: 74398

Gnomad4 AFR AF: 0.345

Gnomad4 AMR AF: 0.609

Gnomad4 ASJ AF: 0.607

Gnomad4 EAS AF: 0.389

Gnomad4 SAS AF: 0.660

Gnomad4 FIN AF: 0.615

Gnomad4 NFE AF: 0.659

Gnomad4 OTH AF: 0.565

Alfa AF: 0.604 Hom.: 5242

Bravo AF: 0.538

TwinsUK AF: 0.649 AC: 2406

ALSPAC AF: 0.662 AC: 2550

ExAC AF: 0.562 AC: 8620

Asia WGS AF: 0.546 AC: 1896 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

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 -

Myoglobinuria, acute recurrent, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	3.5
Dann	Uncertain	0.99
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0000023	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Vest4		0.049
MutPred		0.10		Gain of sheet (P = 0.0827);
MPC		0.16
ClinPred		0.0090	T
GERP RS		-0.51
gMVP		0.069

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4669769; hg19: chr2-11817812; COSMIC: COSV70685987; COSMIC: COSV70685987;