2-11713787-G-A

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.113G>A(p.Arg38Gln) variant causes a missense change. The variant allele was found at a frequency of 0.219 in 1,505,294 control chromosomes in the GnomAD database, including 38,818 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3224 hom., cov: 33)
  • Exomes 𝑓: 0.22 (35594 hom.)
• Consequence: LPIN1 NM_001261428.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:3
• Conservation: PhyloP100: 4.11

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=0.0019290447).
• BP6: Variant 2-11713787-G-A is Benign according to our data. Variant chr2-11713787-G-A is described in ClinVar as [Benign]. Clinvar id is 403045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPIN1	NM_001261428.3	c.113G>A	p.Arg38Gln	missense_variant	2/22
LPIN1	NM_001349208.2	c.113G>A	p.Arg38Gln	missense_variant	2/21
LPIN1	NM_001349207.2	c.81+36059G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPIN1	ENST00000449576.6	c.113G>A	p.Arg38Gln	missense_variant	2/22	2		A2

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27583 AN: 152004 Hom.: 3221 Cov.: 33

Gnomad AFR AF: 0.0434

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.232

Gnomad OTH AF: 0.166

GnomAD3 exomes AF: 0.227 AC: 28792 AN: 126740 Hom.: 3632 AF XY: 0.229 AC XY: 15874 AN XY: 69360

Gnomad AFR exome AF: 0.0383

Gnomad AMR exome AF: 0.281

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.153

Gnomad SAS exome AF: 0.254

Gnomad FIN exome AF: 0.270

Gnomad NFE exome AF: 0.228

Gnomad OTH exome AF: 0.232

GnomAD4 exome AF: 0.223 AC: 301780 AN: 1353172 Hom.: 35594 Cov.: 27 AF XY: 0.225 AC XY: 150184 AN XY: 668858

Gnomad4 AFR exome AF: 0.0361

Gnomad4 AMR exome AF: 0.279

Gnomad4 ASJ exome AF: 0.195

Gnomad4 EAS exome AF: 0.196

Gnomad4 SAS exome AF: 0.257

Gnomad4 FIN exome AF: 0.269

Gnomad4 NFE exome AF: 0.225

Gnomad4 OTH exome AF: 0.211

GnomAD4 genome AF: 0.181 AC: 27582 AN: 152122 Hom.: 3224 Cov.: 33 AF XY: 0.185 AC XY: 13775 AN XY: 74356

Gnomad4 AFR AF: 0.0432

Gnomad4 AMR AF: 0.236

Gnomad4 ASJ AF: 0.206

Gnomad4 EAS AF: 0.173

Gnomad4 SAS AF: 0.261

Gnomad4 FIN AF: 0.276

Gnomad4 NFE AF: 0.232

Gnomad4 OTH AF: 0.163

Alfa AF: 0.222 Hom.: 4075

Bravo AF: 0.172

TwinsUK AF: 0.231 AC: 856

ALSPAC AF: 0.220 AC: 846

ExAC AF: 0.209 AC: 2860

Asia WGS AF: 0.173 AC: 600 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperchloremia Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Phenosystems SA

-

- -

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 -

LPIN1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 02, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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	-0.41	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.10	N
REVEL	Uncertain	0.32
Sift	Benign	0.11	T
Sift4G	Pathogenic	0.0	D
Vest4		0.15
MPC		0.22
ClinPred		0.016	T
GERP RS		4.9
gMVP		0.11

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4614906; hg19: chr2-11853913; COSMIC: COSV71938074;