rs11524

chr2-11826191-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001349206.2(LPIN1):c.*1400T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 152,530 control chromosomes in the GnomAD database, including 5,212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.21 (5212 hom., cov: 32)
  • Exomes 𝑓: 0.042 (0 hom.)
• Consequence: LPIN1 NM_001349206.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.526

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-11826191-T-C is Benign according to our data. Variant chr2-11826191-T-C is described in ClinVar as [Benign]. Clinvar id is 330940.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPIN1	NM_001349206.2	c.*1400T>C		3_prime_UTR_variant	21/21	ENST00000674199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPIN1	ENST00000674199.1	c.*1400T>C		3_prime_UTR_variant	21/21		NM_001349206.2	P4

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31887 AN: 151982 Hom.: 5174 Cov.: 32

Gnomad AFR AF: 0.445

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.0934

Gnomad FIN AF: 0.0571

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.187

GnomAD4 exome AF: 0.0419 AC: 18 AN: 430 Hom.: 0 Cov.: 0 AF XY: 0.0349 AC XY: 9 AN XY: 258

Gnomad4 FIN exome AF: 0.0425

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.210 AC: 31971 AN: 152100 Hom.: 5212 Cov.: 32 AF XY: 0.207 AC XY: 15392 AN XY: 74372

Gnomad4 AFR AF: 0.446

Gnomad4 AMR AF: 0.173

Gnomad4 ASJ AF: 0.225

Gnomad4 EAS AF: 0.167

Gnomad4 SAS AF: 0.0939

Gnomad4 FIN AF: 0.0571

Gnomad4 NFE AF: 0.113

Gnomad4 OTH AF: 0.184

Alfa AF: 0.138 Hom.: 921

Bravo AF: 0.233

Asia WGS AF: 0.132 AC: 462 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myoglobinuria, acute recurrent, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.29
Dann	Benign	0.50

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: rs11524; hg19: chr2-11966317; COSMIC: COSV56764839; COSMIC: COSV56764839;